TOXICOLOGICAL PROFILE FOR MANGANESE AND COMPOUNDS Prepared by: Life Systems, Inc. Under Subcontract to: Clement International Corporation Under Contract No. 205-88-0608 Prepared for: Agency for Toxic Substances and Disease Registry U.S. Public Health Service July 1992 it DISCLAIMER The use of company or product name(s) is for identification only and does not imply endorsement by the Agency for Toxic Substances and Disease Registry. CNY vOR a8 iii FOREWORD The Superfund Amendments and Reauthorization Act (SARA) of 1986 (Public Law 99-499) extended and amended the Comprehensive Environmental Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund). This public law directed the Agency for Toxic Substances and Disease Registry (ATSDR) to prepare toxicological profiles for hazardous substances which are most commonly found at facilities on the CERCLA National Priorities List and which pose the most significant potential threat to human health, as determined by ATSDR and the Environmental Protection Agency (EPA). The lists of the 250 most significant hazardous substances were published in the Federal Register on April 17, 1987; on October 20, 1988; on October 26, 1989; and on October 17, 1990. A revised list of 275 substances was published on October 17, 1991. Section 104(i) (3) of CERCLA, as amended, directs the Administrator of ATSDR to prepare a toxicological profile for each substance on the lists. Each profile must include the following content: (A) An examination, summary, and interpretation of available toxicological information and epidemiological evaluations on the hazardous substance in order to ascertain the levels of significant human exposure for the substance and the associated acute, subacute, and chronic health effects. (B) A determination of whether adequate information on the health effects of each substance is available or in the process of development to determine levels of exposure which present a significant risk to human health of acute, subacute, and chronic health effects. (C) Where appropriate, an identification of toxicological testing needed to identify the types or levels of exposure that may present significant risk of adverse health effects in humans. This toxicological profile is prepared in accordance with guidelines developed by ATSDR and EPA. The original guidelines were published in the Federal Register on April 17, 1987. Each profile will be revised and republished as necessary. The ATSDR toxicological profile is intended to characterize succinctly the toxicological and adverse health effects information for the hazardous substance being described. Each profile identifies and reviews the key literature (that has been peer-reviewed) that describes a hazardous substance’s toxicological properties. Other pertinent literature is also presented but described in less detail than the key studies. The profile is not intended to be an exhaustive document; however, more comprehensive sources of specialty information are referenced. iv Foreword Each toxicological profile begins with a public health statement, which describes in nontechnical language a substance’'s relevant toxicological properties. Following the public health statement is information concerning levels of significant human exposure and, where known, significant health effects. The adequacy of information to determine a substance’s health effects is described in a health effects summary. Data needs that are of significance to protection of public health will be identified by ATSDR, the National Toxicology Program (NTP) of the Public Health Service, and EPA. The focus of the profiles is on health and toxicological information; therefore, we have included this information in the beginning of the document. The principal audiences for the toxicological profiles are health professionals at the federal, state, and local levels, interested private sector organizations and groups, and members of the public. This profile reflects our assessment of all relevant toxicological testing and information that has been peer reviewed. It has been reviewed by scientists from ATSDR, the Centers for Disease Control, the NTP, and other federa. agencies. It has also been reviewed by a panel of nongovernment peer reviewers. Final responsibility for the contents and views expressed in this toxicological profile resides with ATSDR. Olt Roper” William L. Roper, M.P.H. namin ieceator Agency for Toxic Substances and Disease Registry FOREWORD LIST OF FIGURES LIST OF TABLES l, 1. 1. P 1 1. 1 1 1 wns wn = aN 7 CONTENTS UBLIC HEALTH STATEMENT . WHAT IS MANGANESE? HOW MIGHT I BE EXPOSED TO ‘MANGANESE? HOW CAN MANGANESE ENTER AND LEAVE MY BODY? HOW CAN MANGANESE AFFECT MY HEALTH? IS THERE A MEDICAL TEST TO DETERMINE WHETHER 1 HAVE BEEN EXPOSED TO MANGANESE? WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT ‘MADE TO PROTECT HUMAN HEALTH? WHERE CAN I GET MORE INFORMATION? 2. HEALTH EFFECTS 2. 2.2 DISCUSSION OF HEALTH EFFECTS BY "ROUTE OF EXPOSURE 2. 1 3 INTRODUCTION . 2.2.1 Inhalation Exposure RFE RRERPPR Ee ONO UPEFWNHEX ONO UL EWN 2.2.2 ral E 2.2.3 erm CLLLLLWWE NNN NNNNON NBNONIONIODEORNNORONNONSONRDMDBNONNS PUL EWN RRR NNN NNNONNNNNND DNDN N TOXICOKINETICS Death . Systemic. Effects Immunological Effects Neurological Effects Developmental Effects Reproductive Effects Genotoxic Effects Cancer posure Death : Systemic Effects Immunological Effects Neurological Effects Developmental Effects Reproductive Effects Genotoxic Effects Cancer 1 Exposure Death . Systemic Effects Immunological Effects Neurological Effects Developmental Effects Reproductive Effects Genotoxic Effects Cancer 2.3.1 sbgorption iid ix xi WN wm —- Sooo NN 15 15 16 17 17 17 18 18 18 25 25 27 28 28 28 29 29 29 29 29 29 29 29 29 29 29 vi 2.3.1.1 Inhalation Exposure 2.3.1.2 Oral Exposure 2.3.1.3 Dermal Exposure 2.3.2 Distribution : 2.3.2.1 Inhalation Exposure 2.3.2.2 Oral Exposure 2.3.2.3 Dermal Exposure 2.3.3 Metabolism ‘vw oa 2.3.4 Excretion + new Ewa 2.3.4.1 Inhalation Exposure 2.3.4.2 Oral Exposure 2.3.4.3 Dermal Exposure 2.3.4.4 Other Routes of Exposure 2.4 RELEVANCE TO PUBLIC HEALTH . x 2.5 BIOMARKERS OF EXPOSURE AND EFFECT 2.5.1 Biomarkers Used to Identify and/or ‘Quantify Exposure “to Manganese ‘ 2.5.2 Biomarkers Used to ‘Characterize Effects Caused ‘by Manganese 2.6 INTERACTIONS WITH OTHER CHEMICALS : 2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE : 2.8 MITIGATION OF EFFECTS 2.9 ADEQUACY OF THE DATABASE . 2.9.1 Existing Information on Health ‘Effects "of Manganese 2.9.2 Data Needs 2.9.3 On-going Studies CHEMICAL AND PHYSICAL INFORMATION . 3.1 CHEMICAL IDENTITY 3.2 PHYSICAL AND CHEMICAL PROPERTIES PRODUCTION, IMPORT, USE, AND DISPOSAL . 4.1 PRODUCTION . 4.2 IMPORT/EXPORT 4.3 USE “ = 4.4 DISPOSAL . POTENTIAL FOR HUMAN EXPOSURE 5.1 OVERVIEW . . 5.2 RELEASES TO THE ENVIRONMENT 5.2.1 Air 5.2.2 Water 5.2.3 Soil ‘ 5.3 ENVIRONMENTAL FATE . 5.3.1 Transport and Partitioning 5.3.2 Transformation and Degradation 5.3.2.1 Air 5.3.2.2 Water 5.3.2.3 Boll . 5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT . 5.4.1 Air 5.4.2 Water 5.4.3 Soil 29 30 30 30 32 32 32 34 34 34 35 35 35 35 45 45 47 47 48 49 52 52 52 59 63 63 63 67 67 69 69 71 71 71 75 75 76 76 76 78 78 78 78 78 78 78 80 vii 5.4.4 Other Environmental Media GENERAL POPULATION AND OCCUPATIONAL EXPOSURE POPULATIONS WITH POTENTIALLY HIGH EXPOSURES ADEQUACY OF THE DATABASE 5.7.1 Data Needs 5.7.2 On-going Studies wun Noy ANALYTICAL METHODS 6.1 BIOLOGICAL MATERIALS 6.2 ENVIRONMENTAL SAMPLES 6.3 ADEQUACY OF THE DATABASE 6.3.1 Data Needs 6.3.2 On-going Studies 7. REGULATIONS AND ADVISORIES 8. REFERENCES 9. GLOSSARY APPENDICES A. USER'S GUIDE . B. ACRONYMS, ABBREVIATIONS, AND SYMBOLS C. PEER REVIEW. 80 82 84 84 84 87 89 89 91 91 93 93 95 99 133 2-1 2-2 2-3 5-1 ix LIST OF FIGURES Levels of Significant Exposure to Manganese - Inhalation . Levels of Significant Exposure to Manganese - Oral Existing Information on Health Effects of Manganese Frequency of NPL Sites with Manganese Contamination 12 22 53 72 2-1 2-2 2-3 2-4 2-5 2-6 2-7 3-1 3-2 5-2 5-3 5-4 6-2 7-1 xi LIST OF TABLES Levels of Significant Exposure to Manganese - Inhalation . Levels of Significant Exposure to Manganese - Oral Normal Manganese Levels in Human and Animal Tissues Tissue Levels in Rats After Oral Exposure to Manganese Genotoxicity of Manganese In Vitro . Genotoxicity of Manganese In Vivo On-going Studies on Manganese Chemical Identity of Manganese Physical and Chemical Properties of Manganese Facilities that Manufacture or Process Manganese and Compounds Releases to the Environment from Facilities that Manufacture or Process Manganese and Compounds Average Levels of Manganese in Ambient Air Manganese Concentrations in Selected Foods Summary of Typical Human Exposure to Manganese Analytical Methods for Determining Manganese in Biological Materials Analytical Methods for Determining Manganese in Environmental Samples Regulations and Guidelines Applicable to Manganese 19 21 33 43 44 60 64 65 68 73 79 81 83 90 92 96 1. PUBLIC HEALTH STATEMENT This Statement was prepared to give you information about manganese and to emphasize the human health effects that may result from exposure to it. The Environmental Protection Agency (EPA) has identified 1,177 sites on its National Priorities List (NPL). Manganese has been found in at least 148 of these sites. However, we do not know how many of the 1,177 NPL sites have been evaluated for manganese. As EPA evaluates more sites, the number of sites at which manganese is found may change. This information is important for you to know because manganese may cause harmful health effects and because these sites are potential or actual sources of human exposure to manganese. When a chemical is released from a large area, such as an industrial plant, or from a container, such as a drum or bottle, it enters the environment as a chemical emission. This emission, which is also called a release, does not always lead to exposure. You can be exposed to a chemical only when you come into contact with the chemical. You may be exposed to it in the environment by breathing, eating, or drinking substances containing the chemical or from skin contact with it. If you are exposed to a hazardous chemical such as manganese, several factors will determine whether harmful health effects will occur and what the type and severity of those health effects will be. These factors include the dose (how much), the duration (how long), the route or pathway by which you are exposed (breathing, eating, drinking, or skin contact), the other chemicals to which you are exposed, and your individual characteristics such as age, sex, nutritional status, family traits, life style, and state of health. 1.1 WHAT IS MANGANESE? Manganese is a naturally occurring substance found in many types of rock. Pure manganese is a silver-colored metal, somewhat like iron in its physical and chemical properties. Manganese does not occur in the environment as the pure metal. Rather, it occurs combined with other chemicals such as oxygen, sulfur, and chlorine. These forms (called compounds) are solids that do not evaporate. However, small dust particles of the solid material can become suspended in air. Some manganese compounds can dissolve in water, and low levels of these compounds are normally present in lakes, streams, and the ocean. Manganese can change from one compound to another (either by natural processes or by man’s activities), but it does not break down or disappear in the environment. Rocks containing high levels of manganese compounds are mined and used to produce manganese metal. This manganese metal is mixed with iron to make various types of steel. Some manganese compounds are used in the production of batteries, as an ingredient in some ceramics, pesticides, and fertilizers, and in dietary supplements. More information on the properties and uses of manganese and how it behaves in the environment may be found in Chapters 3, 4, and 5. 2 1. PUBLIC HEALTH STATEMENT 1.2 HOW MIGHT I BE EXPOSED TO MANGANESE? Because manganese is a natural component in the environment, you are always exposed to low levels of it in water, air, soil, and food. In drinking water, levels are usually about 0.004 parts manganese per million parts of water (ppm). In air, levels are usually about 0.02 micrograms manganese per cubic meter of air (ug/m®). Levels in soil usually range from 40 to 900 ppm. Manganese is also a normal component of living things, including both plants and animals, so manganese is present in foods. For nearly all people, food is the main source of manganese, and usual daily intakes range from about 2,000 to 9,000 ug/day. The exact amount you take in depends on your diet. You are most likely to be exposed to higher-than-normal levels of manganese if you work in a factory where manganese metal is produced from manganese ores, or where manganese compounds are used to make steel or other products. In these factories, you would be exposed to manganese mainly by breathing in manganese dust. If you live near such a factory, you could also be exposed to higher-than-average levels of manganese dust in the outside air, although the amounts would be much lower than in the factory. You might be exposed to higher-than-average levels if you live near a coal or oil-burning factory, or close to a major highway, because manganese is released into air when fossil fuels are burned. If manganese compounds from a factory or a waste site get into water, you could be exposed to higher-than-average levels by drinking the water. More information on how you might be exposed to manganese or its compounds is given in Chapter 5. 1.3 HOW CAN MANGANESE ENTER AND LEAVE MY BODY? If you live near a hazardous waste site, you could be exposed to manganese in soil or water, or to manganese-containing dust particles in air. If you get manganese-contaminated soil or water on your skin, very little will enter your body, so this is not of concern. If you swallow manganese in water or in soil, most of the manganese is excreted in the feces. However, about 3%-5% is usually taken up and kept in the body. If you breathe air containing manganese dust, many of the dust particles will be trapped in your lungs. Some of the manganese in these particles may then dissolve in the lungs and enter the blood. The exact amount that does this is not known. Particles that do not dissolve will be carried in a sticky layer of mucus out of the lungs to the throat, where they will be swallowed into the stomach. Because manganese is a regular part of the human body, the body normally controls the amount that is taken up and kept. For example, if large amounts are eaten in the diet, the amount that is taken up in the body becomes smaller. If too much does enter the body, the excess is usually removed in the feces. Therefore, the total amount of manganese in the body usually tends to stay about the same, even when exposure rates are higher or lower than usual. However, if too much manganese is taken in, the body may not be able to adjust for the added amount. 3 1. PUBLIC HEALTH STATEMENT More information on how manganese enters and leaves the body is given in Chapter 2. 1.4 HOW CAN MANGANESE AFFECT MY HEALTH? Eating a small amount of manganese each day is important in maintaining your health. The amount of manganese in a normal diet (about 2,000-9,000 pg/day) seems to be enough to meet your daily need, and no cases of illness from eating too little manganese have been reported in humans. In animals, eating too little manganese can interfere with normal growth, bone formation, and reproduction. Too much manganese, however, can cause serious illness. Although there are some differences between different kinds of manganese, most manganese compounds seem to cause the same effects. Manganese miners or steel workers exposed to high levels of manganese dust in air may have mental and emotional disturbances, and their body movements may become slow and clumsy. This combination of symptoms is a disease called manganism. Workers usually do not develop symptoms of manganism unless they have been exposed for many months or years. Manganism occurs because too much manganese injures a part of the brain that helps control body movements. Some of the symptoms of manganism can be reduced by medical treatment, but the brain injury is permanent. It is not certain whether eating or drinking too much manganese can cause manganism or not. In one report, humans who drank water containing high levels of manganese developed symptoms similar to those seen in manganese miners or steel workers, but it is not certain if the effects were caused by manganese alone. In another report, people who drank water with above average levels of manganese seemed to have a slightly higher frequency of symptoms such as weakness, stiff muscles, and trembling of the hands. However, these symptoms are not specific for manganese, and might have been caused by other factors. Studies in animals have shown that very high levels of manganese in food or water can cause changes in the brain. This information suggests that high levels of manganese in food or water might cause brain injury, but it does not appear that this is of concern to people exposed to the normal amounts of manganese in food, water, or air. The chances of harm from exposure near a waste site can only be evaluated on a site-by-site basis. Breathing too much manganese dust can also cause irritation of the lungs. Sometimes this makes breathing difficult and it can also increase the chances of getting a lung infection, such as pneumonia. However, this can happen from breathing in many different kinds of dust particles, not just those that contain manganese. A common effect in men who are exposed to high levels of manganese dust in air is impotence. As a result, men exposed to high levels may not be able to father children. Studies in animals show that too much manganese may also injure the testes. Much less is known about the effects of too much manganese in women. Studies in animals suggest that females may not be as sensitive to manganese as males, but this is not certain. 4 1. PUBLIC HEALTH STATEMENT There is not much information on whether manganese can cause birth defects. One study in humans suggests that high exposures to manganese in the environment might increase the chances of birth defects, but other factors besides manganese might have been responsible. One study in animals shows that exposure of pregnant females to high levels of manganese in air can lead to changes in behavior of the offspring. Since there are so few studies on this, more research is needed to determine the importance of these observations. No studies have been done to determine if breathing manganese dust causes cancer. Some studies in animals suggest that eating high amounts of manganese might increase the chances of getting cancer. However, only a few animals in these studies got cancer, and it was difficult to tell if the tumors were really caused by the excess manganese. Thus, there is little evidence to suggest that cancer is a major concern for people exposed to manganese in the environment or near waste sites. The EPA has determined that manganese is not classifiable as to human carcinogenicity. There is no information on any human or animal health effects from skin contact with manganese. More information on health effects of manganese in humans and animals can be found in Chapter 2. 1.5 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO MANGANESE? Several tests are available for measuring manganese in blood, urine, hair, or feces. Because manganese is a normal part of the body, some manganese is always found in these materials. Concentrations of manganese in blood, urine, hair, or feces are often found to be higher-than-average in groups of people exposed to above-average levels of manganese. However, because the levels in different people can vary widely, these methods are not very reliable for determining if any one individual has been exposed to higher-than-average levels of manganese. Also, because excess manganese is usually removed from the body within a few days, past exposures to manganese are difficult to measure. For these reasons, it is often not possible to tell whether excess exposure to manganese has occurred, or whether there is reason for health concern. More information of how manganese can be measured in exposed humans can be found in Chapters 2 and 6. 1.6 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN HEALTH? In order to avoid staining of clothing or fixtures, the EPA recommends that the concentration of manganese in drinking water not be more than 0.05 ppm. The Food and Drug Administration (FDA) has set the same level for bottled water. This concentration is believed to be more than adequate to 5 1. PUBLIC HEALTH STATEMENT protect human health. The EPA has also established rules that set limits on the amount of manganese that factories can dump into water, and requires factories that use or produce manganese to report how much they dump in the environment to the EPA. The Occupational Safety and Health Administration (OSHA) has set a limit of 1,000 ug/m’ for the average amount of manganese in workplace air over an 8-hour workday. More information on governmental rules regarding manganese can be found in Chapter 7. 1.7 WHERE CAN I GET MORE INFORMATION? If you have any more questions or concerns not covered here, please contact your state health or environmental department or: Agency for Toxic Substances and Disease Registry Division of Toxicology 1600 Clifton Road, E-29 Atlanta, Georgia 30333 This agency can also provide you with information on the location of the nearest occupational and environmental health clinic. Such clinics specialize in recognizing, evaluating, and treating illnesses that result from exposure to hazardous substances. 2. HEALTH EFFECTS 2.1 INTRODUCTION The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and other interested individuals and groups with an overall perspective of the toxicology of inorganic manganese compounds and a depiction of significant exposure levels associated with various adverse health effects. It contains descriptions and evaluations of studies and presents levels of significant exposure for manganese based on toxicological studies and epidemiological investigations. Emphasis has been placed on the health effects of compounds containing inorganic manganese in the +2, +3, or +4 valence states, since these are the forms most often encountered in the environment and in the workplace. Although available data are limited, it does not appear that there are large differences in the toxic effects of these compounds except after acute exposure to extremely high doses. Since such high dose exposures are unlikely to occur in the general population or people living near waste sites, no distinction is made in the text between various inorganic Mn(+2), Mn(+3), or Mn(+4) compounds, although the chemical form used in a study is reported when it is known. Manganese in the form of permanganate (MnO,”) produces toxic effects primarily through its oxidizing capacity. However, because of its tendency to oxidize organic material, permanganate ion is not stable in the environment, and the probability of exposure to this species around waste sites is considered very low. For this reason, data on exposures to permanganate are discussed only briefly. Another form of manganese of potential concern is the organic compound methylcyclopentadienyl manganese tricarbonyl (MMT). This is a synthetic compound used as an additive in unleaded gasoline and as a smoke abater for diesel engines. However, no evidence was located to show that MMT is present in soil or groundwater at waste sites (although MMT is not usually analyzed for). Moreover, burning of MMT releases inorganic oxides rather than MMT into air, and the effects of these oxides are discussed in this report. For these reasons, the health effects of MMT itself (injury to lung, liver, and kidney) are not considered here. 2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE To help public health professionals address the needs of persons living or working near hazardous waste sites, the information in this section is organized first by route of exposure--inhalation, oral, and dermal--and then by health effect--death, systemic, immunological, neurological, developmental, reproductive, genotoxic, and carcinogenic effects. These data are discussed in terms of three exposure periods--acute (less than 15 days), intermediate (15-364 days), and chronic (365 days or more). Levels of significant exposure for each route and duration are presented in tables and illustrated in figures. The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowest-observed-adverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the 8 2. HEALTH EFFECTS studies. LOAELs have been classified into "less serious" or "serious" effects. These distinctions are intended to help the users of the document identify the levels of exposure at which adverse health effects start to appear. They should also help to determine whether or not the effects vary with dose and/or duration, and place into perspective the possible significance of these effects to human health. The significance of the exposure levels shown in the tables and figures may differ depending on the user's perspective. For example, physicians concerned with the interpretation of clinical findings in exposed persons may be interested in levels of exposure associated with "serious" effects. Public health officials and project managers concerned with appropriate actions to take at hazardous waste sites may want information on levels of exposure associated with more subtle effects in humans or animals (LOAEL) or exposure levels below which no adverse effects (NOAEL) have been observed. Estimates of levels posing minimal risk to humans (Minimal Risk Levels, MRLs) may be of interest to health professionals and citizens alike. Estimates of exposure levels posing minimal risk to humans (MRLs) have been made, where data were believed reliable, for the most sensitive noncancer effect for each exposure duration. MRLs include adjustments to reflect human variability from laboratory animal data to humans. Although methods have been established to derive these levels (Barnes et al. 1988; EPA 1989a), uncertainties are associated with these techniques. Furthermore, ATSDR acknowledges additional uncertainties inherent in the application of the procedures to derive less than lifetime MRLs. As an example, acute inhalation MRLs may not be protective for health effects that are delayed in development or are acquired following repeated acute insults, such as hypersensitivity reactions, asthma, or chronic bronchitis. As these kinds of health effects data become available and methods to assess levels of significant human exposure improve, these MRLs will be revised. 2.2.1 Inhalation Exposure Inorganic manganese compounds are not volatile, but they can exist in air as aerosols or suspended particulate matter. Table 2-1 and Figure 2-1 summarize available quantitative information on health effects that have been observed in humans and animals following inhalation exposure to various manganese compounds. All exposure levels are expressed as milligrams of manganese per cubic meter (mg manganese,/m’) . 2.2.1.1 Death No studies were located regarding death in humans or animals after inhalation exposure to manganese. TABLE 2-1. Levels of Significant Exposure to Manganese - Inhalation Exposure LOAEL® (effect) Key to frequency/ NOAEL® Less serious Serious figure? Species duration System (mg/m?) (mg/m?) (mg /m’) Reference Form ACUTE EXPOSURE Systemic 1 Rat 10 d Resp 43 (inflammation, Shiotsuka 1984 MnO, 6hr/d increased lung weight) Hemato 138 Other 138 2 Gn pig 1d Resp 14 Bergstrom 1977 MnO, 24hr/d 3 Mouse 1-4 days Resp 69 (pneumonia) Maigetter et al. MnO, 3hr/d 1976 4 Mouse 2 hr Resp 2.8 Adkins et al. Mn,0, 1980b INTERMEDIATE EXPOSURE Systemic 5 Rat 9 mo Resp 1.1 Ulrich et al. Mn,0, (cont) Hemato 1.1 1979b Hepatic 1.1 Other 1.1 6 Rabbit 4 wk Resp 3.9 Camner et al. MnCl, 5d/wk 1985 6hr/d 7? Monkey 9 mo Resp 1.1 Ulrich et al. Mn,0, (cont) 1979a 8 Monkey 10 mo Resp 0.7 (mild Suzuki et al. MnO, 22 hr/d inflammation) 1978 Neurological 9 Rat 9 mo 21 Ulrich et al. Mn,0, (cont) 1979b 10 Mouse 16-32 wk 72 (altered behavior) Morganti et al. MnO, 5d/wk 1985 7hr/d C S1DHJ4d HLITVIH TABLE 2-1 (Continued) Exposure LOAEL® (effect) Key to frequency/ NOAEL® Less serious Serious figure® Species duration System (mg/m) (mg/m?) (mg/m?) Reference Form 11 Mouse 18 wk 61 (altered behavior) Lown et al. 1984 MnO, 5d /wk 7hr/d 12 Monkey 23 wk 5 Coulston and Mn,0, 23hr/d Griffin 1977 13 Monkey 9 mo 1.1 Ulrich et al. Mn,0, (cont) 1979a Developmental 14 Mouse 18 wk 61 (decreased pup Lown et al. 1984 MnO, 5d /wk weight, altered I 7hr/d behavior) . Reproductive produ = 15 Mouse 18 wk 61 Lown et al. 1984 MnO, > 5d/wk rr 7hr/d H m CHRONIC EXPOSURE i = Systemic QQ a 16 Human No data Resp 3.6 (pneumonia) Lloyd Davies MnO, (occup) 1946 17 Human 1-19 yr Resp 0.97 (cough, decreased Roels et al. Mn (occup) lung function) 1987a salts Hemato 0.97 and oxides 18 Monkey 66 wk Hemato 0.1 Coulston and Mn,0, Griffin 1977 Neurological 19 Human 1-9 yr 6° (psychomotor Schuler et al. MnO, (occup) disturbances. 1957 weakness, pain) 20 Human 2 yr 28 (bradykinesia) Huang et al. MnO, (occup) 1989 21 Human No data 5 (weakness, ataxia, Tanaka and No (occup) pain) Lieben 1969 data 01 TABLE 2-1 (Continued) Exposure LOAEL® (effect) Key to frequency/ NOAEL® Less serious Serious figure’ Species duration System (mg/m?) (mg/m?) (mg/m?) Reference Form 22 Human No data 2.6 (tremor, decreased Saric et al. No (occup) reflexes) 1977 data 23 Human No data 22° (bradykinesia, Cook et al. 1974 No (occup) mask-like face) data 24 Human 1-35 yr 0.14° (decreased Iregren 1990 MnO, (9.9 reaction time, ave) finger tapping) (occup) 25 Human 1-19 yr 0.97 (altered reaction Roels et al. Mn (occup) time, short-term 1987a salts memory, decreased and hand steadiness) oxides rN 26 Human 1 yr 3.5 (weakness, ataxia) Whitlock et al. No (occup) 1966 data BE > 27 Monkey 2 yr 30 (altered DOPA Bird et al. 1984 MnO, Ld 5d /wk levels) 5 6hr/d m 28 Monkey 66 wk 0.1 Coulston and Mn,0, 2 Griffin 1977 = 3 Reproductive wn 29 Human 1-19 yr 0.97 (decreased Lauwerys et al. Mn (occup) fertility in 1985 salts males) and oxides “The number corresponds to entries in Figure 2-1. "All doses expressed as mg manganese /m’. “Used to derive a chronic inhalation MRL of 0.0003 mg/m’; dose adjusted for intermittent exposure (5 days/week, 8 hours/day), and divided by an uncertainty factor of 100 (10 for use of a LOAEL, and 10 for human variability). ave = average: cont = continuous; d = day(s); DOPA = dihydroxyphenylalanine; Gn pig = Guinea pig; Hemato = Hematological; hr = hour(s): LOAEL = lowest-observed-adverse-effect level: Mn = manganese; Mn,0, = manganese tetroxide; MnO, = manganese dioxide; MnCl, = manganous chloride; mo = month(s); NOAEL = no-observed-adverse-effect level; occup = occupational; Resp = respiratory; wk = week(s); yr = year(s) 11 (mg/m3) 1,000 100 10 0.1 0.01 0.001 0.0001 FIGURE 2-1. Levels of Significant Exposure to Manganese — Inhalation g Guinea pig A LOAEL for serious effects (humans) k Monkey A LOAEL for less serious effects (humans) /\ NOAEL (humans) The number next to each point corresponds to entries in Table 2-1. ACUTE INTERMEDIATE (<14 Days) (15-364 Days) Systemic Systemic \ A > AO © Ng 3° oS & ® Fo © CA & & & & o& SF &° oF KF & Ff & Orr Orr 3 so Q1r Bron tim @14m (Qi5m O2 On O12 O4m 7 Qsr Osr Osr Osr O13 Ow 8k Key & 3 3 r Rat LOAEL for serious pHocts {arimais) 3 Within rik tevel Tor m Mouse (D LOAEL for less serious effects (animals) | effects other than cancer h Rabbit ~~ O NOAEL (animals) w C S1034dd HLTIVIH ct (mg/m3) 1,000 100 10 0.1 0.01 0.001 0.0001 ps FIGURE 2-1 (Continued) CHRONIC (>365 Days) >»

(Cook et al. 1974; Huang et al. 1989; Iregren 1990; Roels et al. 1987a; Saric et al. 1977; Schuler et al. 1957; Tanaka and Lieben 1969; Whitlock et al. 1966). Although these studies are not adequate to define the dose-response curve or the threshold for neurotoxicity exactly, the study by Iregren (1990) used neurobehavioral tests to identify early effects of manganese in workers exposed to an estimated median concentration level of 0.14 mg manganese /m>. This value is supported by the study by Roels et al. (1987a) who detected early neurological effects in workers exposed to 1 mg manganese/m>. The lower LOAEL (0.14 mg manganese/m>) has been used to calculate a chronic inhalation MRL of 0.0003 mg manganese/m> (0.3 pg manganese/m’), as described in footnote c¢ in Table 2-1. Intermediate or chronic inhalation exposure of animals to manganese dusts usually does not produce neurological signs similar to those seen in humans, either in monkeys (Bird et al. 1984; Coulston and Griffin 1977; Ulrich et al. 1979a) or rats (Ulrich et al. 1979b). Behavioral tests (especially those that involve measurements of physical activity) have detected signs of neurological effects in mice, although these are only seen at relatively high exposure levels (60-70 mg manganese/m*)» (Lown et al. 1984; Morganti et al. 1985). 2.2.1.5 Developmental Effects Very little information is available on the developmental effects of manganese. The incidence of birth defects has been investigated in a small population of people living on an island where environmental levels of manganese are high (Kilburn 1987), but control data were not provided and the study population was too small to determine if the observed incidence of birth 17 2. HEALTH EFFECTS defects was higher than expected. In animals, exposure of mice to an average of 61 mg manganese/m’ (as Mn0O,) for 16 weeks prior to gestation led to a decrease in average pup weight at birth and decreased activity levels (rearing, exploration) in the pups (Lown et al. 1984). This suggests that maternal exposure to manganese may lead to neurological effects in the fetus or the neonate, but the data do not define the dose-response curve, and the biological consequence of these effects is not certain. 2.2.1.6 Reproductive Effects As discussed earlier (see Section 2.2.1.4), impotence and loss of libido are common symptoms in male workers afflicted with clinically identifiable signs of manganism (Emara et al. 1971; Mena et al. 1967; Rodier 1955; Schuler et al. 1957). Obviously this could lead to reduced reproductive success in men, and impaired fertility (measured as a decreased number of children per married couple) has been observed in male workers exposed to manganese dust, even at levels that did not produce frank manganism (Lauwreys et al. 1985). This suggests that impaired sexual function in men may be one of the earliest clinical manifestations of manganism, but no dose-response information was presented so it is not possible to define a threshold for this effect. Intratracheal instillation studies in rabbits indicate that single high doses of manganese (160 mg/kg, as MnO,) can cause severe degenerative changes in the seminiferous tubules and lead to sterility (Chandra et al. 1973; Seth et al. 1973). This effect did not occur immediately, but developed slowly over the course of 4-8 months following the exposure. Direct damage to the testes has not been reported in occupationally exposed humans, suggesting that this effect may not be of concern under typical exposure circumstances. However, specific studies to investigate possible testicular damage have not been reported. No studies were located regarding effects on women or female animals following inhalation exposure to manganese. The highest NOAEL values and all reliable LOAEL values for reproductive effects in each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1. 2.2.1.7 Genotoxic Effects No studies were located regarding genotoxic effects in humans or animals following inhalation exposure to manganese. Other genotoxicity studies are discussed in Section 2.4. 2.2.1.8 Cancer No studies were located regarding carcinogenic effects in humans or animals following inhalation exposure to manganese. 18 2. HEALTH EFFECTS 2.2.2 Oral Exposure Although humans are often exposed to significant quantities of manganese compounds in food and water (see Sections 5.4 and 5.5), reports of adverse effects in humans from ingestion of manganese are rare. Most information on the effects of oral exposure to manganese is derived from studies in animals. These studies are summarized in Table 2-2 and Figure 2-2, and the findings are discussed below. All doses are expressed as mg manganese/kg/day. 2.2.2.1 Death Only one study was located in which death in humans may have been associated with ingestion of manganese (Kawamura et al. 1941). In this report, death from "emaciation" occurred in two adults who ingested drinking water contaminated with high levels of manganese. However, as discussed in detail in Section 2.2.2.4, several aspects of this incident suggest that manganese may not have been responsible for the deaths. In animals, most studies indicate that manganese compounds have low acute oral toxicity. With exposure via feed, daily oral doses of 930 mg manganese/kg/day (as manganous sulfate, MnSO,) did not cause significant mortality in rats until after 16 months of exposure (Hejtmancik et al. 1987a), and chronic exposure of mice to 810 mg manganese/kg/day (as MnSO,) did not cause increased mortality within 24 months (Hejtmancik et al. 1987b). Similarly, doses as high as 2,300 mg manganese/kg/day (as manganous chloride, MnCl,) in the diet were tolerated for 6 months without lethality (Gianutsos and Murray 1982). In contrast to these studies, when exposure is by gavage (usually as highly concentrated solutions of MnCl, in water), measured LDs, values for 1-21 days of exposure range from 225 to 820 mg manganese /kg/day (Kostial et al. 1978; Rehnberg et al. 1980; Smyth et al. 1969). This suggests that gavage dosing with a bolus of a concentrated soluble manganese compound in water is not a good model for determining the toxic effects of manganese ingested over the course of a day in food, soil, or drinking water at the concentrations likely to be encountered near waste sites. The highest NOAEL values and all reliable LOAEL values for lethality in each species and duration category are recorded in Table 2-2 and plotted in Figure 2-2. 2.2.2.2 Systemic Effects Studies in animals provide limited data regarding the effects of manganese ingestion on systemic target tissues. This information is discussed below. Table 2-2 and Figure 2-2 present the highest NOAEL and all reliable LOAEL values for these effects for each species and each duration category. TABLE 2-2. Levels of Significant Exposure to Manganese - Oral LOAEL® (effect) Exposure Key to frequency/ NOAEL® Less serious Serious figure? Species Route duration System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference Form ACUTE EXPOSURE Death 1 Rat (GW) 1x 820 (LD50) Smyth et al. Mn 1969 acet. 2 Rat (GW) 1x 804 (LD50 - 8 days) Kostial et al. MnCl, 1978 3 Rat (GW) 1x 410 (LD50 - MnCl,) Holbrook et al. MnCl, 1975 MnO, INTERMEDIATE EXPOSURE Death 4 Rat (GW) 21d 225 (LD50 - 21 days) Rehnberg et al. Mn,0, 1980 5 Mouse (F) 6 mo 2300 Gianutsos and MnCl, Murray 1982 Systemic 6 Rat (W) 10 wk Hepatic 12 Wassermann and MnCl, Wassermann 1977 7 Rat (F) 224 d Hemato 180 Carter et al. Mn,0, 1980 8 Mouse (F) 90 d Hepatic 140 Gray and Laskey Mn,0, Renal 140 1980 Neurological 9 Rat (GW) 24 d 1 10 (decreased Deskin et al. MnCl, (Neonatal) dopamine levels 1980 in hypothalamus, altered enzyme levels) 10 Rat (GW) 44 d 150 (ataxia) Kristensson MnCl, et al. 1986 11 Rat (W) 100- 390 (altered Eriksson et al. MnCl, 265 d neurotransmitter 1987a levels) C SLO3Add HLIVHH 61 TABLE 2-2 (Continued) LOAEL® (effect) et al. 1987b Exposure Key to frequency/ NOAEL® Less serious Serious figure? Species Route duration System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference Form 12 Rat (W) 2 mo 600 (increased GABA Bonilla 1978b MnCl, levels) 13 Rat (W) 30d 140 (altered behavior, Chandra 1983 MnCl, altered neurotransmitter levels) 14 Rat (W) 8 mo 14 (altered Bonilla and MnCl, neurotransmitter Prasad 1984 levels) i5 Rat (GO) 14-21 d 22 Kontur and MnCl, Fechter 1988 16 Rat (GW) 60 4d 1 (neuronal Chandra and MnCl, (Neonatal) degeneration, Shukla 1978 altered brain enzymes) 17 Mouse (F) 6 mo 2300 (decreased Gianutsos and MnCl, dopamine levels) Murray 1982 18 Mouse (F) 90 d 140 (decreased Gray and Laskey Mn,0, activity) 1980 Reproductive 19 Rat (F) 100-224d 13 (reduced Laskey et al. Mn,0, testosterone 1982 levels) 20 Rat (W) 20 d 620 1240 (decreased litter Kontur and MnCl, Gd 0-20 weight) Fechter 1988 21 Mouse (F) 90 d 140 (delayed growth Gray and Laskey Mn,0, of testes) 1980 CHRONIC EXPOSURE Death 22 Rat (F) 103 wk 290 930 Hejtmancik MnSO, et al. 1987a 23 Mouse (F) 103 wk 810 He jtmancik MnSO, C S10d44d HLTVIH 0c TABLE 2-2 (Continued) ball acet (GO) = acetate; Cardio = cardiovascular; doses expressed as mg manganese/kg/day. lowest-observed-adverse-effect level; Mn = manganese; MnCl, = manganous chloride; MnO, = manganese dioxide; Mn,0, = manganese tetroxide; MnSO, = manganous sulfate; mo = month(s); Musc/skel = Musculoskeletal; NOAEL = no-observed-adverse-effect level; Resp = respiratory; (W) = water; wk = week(s); x = time; year(s) Exposure LOAEL® (effect) Key to frequency/ NOAEL® Less serious Serious figure? Species Route duration System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference Form Systemic 24 Rat (F) 103 wk Resp 930 He jtmancik MnSO, Cardio 930 et al. 1987a Gastro 930 Hemato 930 Musc/skel 930 Hepatic 930 Renal 930 Derm/oc 930 25 Mouse (F) 103 wk Resp 810 He jtmancik MnSO, Cardio 810 et al. 1987b Gastro 250 810 (hypertrophy) Hemato 810 Musc/skel 810 Hepatic 810 Renal 810 Derm/oc 810 Neurological 26 Human (W) 50 yr 0.059 (mild neurological Kondakis et al. No signs) 1989 data 27 Rat (W) 2 yr 40 (altered Lai et al. 1984 MnCl, neurotransmitter uptake) 28 Rat (W) 65 wk 40 (increased Nachtman et al. MnCl, activity) 1986 29 Monkey (GW) 18 mo 25 (weakness, Gupta et al. MnCl, rigidity) 1980 “The number corresponds to entries in Figure 2-2. cont = continuous; d = day(s); Derm/oc = dermal/ocular; (F) = feed; Gd = gestation day; = gavage - oil; (GW) = gavage - water; GABA = gamma amino butyric acid; Gastro = gastrointestinal; Hemato = hematological; LD50 = lethal dose (50% kill); LOAEL = C SIDHAdd HLIVHIH 1¢ FIGURE 2-2. Levels of Significant Exposure to Manganese — Oral ACUTE INTERMEDIATE (<14 Days) (15-364 Days) > . > 2 & “O & $ & 3 & & & © © 2 < Q @ 2 Q Q Q > is S (mg/kg/day) ~ ¢ 10,000 — Osm @17m fm @ 20r 1,000 Hr BH QQ rer O2or | El Q ir @« On 10r 100 — Osm Osm @ 18m @1r (P2im 15r 10 Os a Por § low Qo Qrer Key 0.1 r Rat HM LD50 m Mouse @ LOAEL for serious effects (animals) 0.01 — k Monkey ( LOAEL for less serious effects (animals) ’ (OO NOAEL (animals) A LOAEL for less serious effects (humans) The number next to each point corresponds to entries in Table 2-2. C S10d44d HITIVIH ¢¢ (mg/kg/day) 10,000 1,000 100 10 0.1 0.01 FIGURE 2-2 (Continued) CHRONIC (>365 Days) Systemic 3 Ny 2 2 3 5 s £ I & & &° ° & 8° WZ & o° © © © J > » © © > N NN 3 2 & > R O > & g &L & & S QQ 2 ® 0° Sd W» WE © © Ng O22 Oz O24 O25? Fas? Oz? O25? O25? O25? O2sf? Q2r O25m ar (P 2s a: rp 28r Key r Rat Ml LD50 Az m Mouse @ LOAEL for serious effects (animals) k Monkey (J LOAEL for less serious effects (animals) (OO NOAEL (animals) A LOAEL for less serious effects (humans) The number next to each point corresponds to entries in Table 2-2. C S1LDHAJd HLIVIH £¢ 24 2. HEALTH EFFECTS Respiratory Effects. No studies were located regarding respiratory effects in humans following oral exposure to manganese. In animals, no histological effects on lung or any clinical signs of impaired respiratory functions were observed in mice or rats exposed to average oral doses of 810 or 930 mg manganese/kg/day (as MnSO,) for 2 years, respectively (Hejtmancik et al. 1987a, 1987b). Cardiovascular Effects. No studies were located regarding cardiovascular effects in humans following oral exposure to manganese. In animals, no histological effects on heart or blood vessels were observed in mice or rats exposed to average oral doses of 810 or 930 mg manganese/kg/day (as MnSO,) for 2 years, respectively (Hejtmancik et al. 1987a, 1987b). Gastrointestinal Effects. No studies were located regarding gastrointestinal effects in humans following oral exposure to manganese, except for one case report of a child who accidentally ingested some potassium permanganate (Southwood et al. 1987). This led to severe local corrosion of the mouth, esophagus, and stomach, but there was no evidence of systemic toxicity. In animals, no histological effects on the gastrointestinal system were observed in rats given oral doses of 930 mg manganese/kg/day (as MnSO,) for 2 years (Hejtmancik et al. 1987a), although mild acanthosis (epithelial hypertrophy) was noted in the forestomach of mice receiving 810 mg manganese/kg/day (Hejtmancik et al. 1987b). This was judged by the authors to be a result of direct irritation of the gastrointestinal epithelium, and to be of minor consequence. Hematological Effects. No studies were located regarding hematological effects in humans following oral exposure to manganese. In animals, no significant hematological effects were observed in mice exposed to 180 mg manganese/kg/day (as Mn,;0,) for 224 days (Carter et al. 1980), or in mice or rats exposed to average oral doses of 810 or 930 mg manganese/kg/day (as MnSO,) for 2 years, respectively (Hejtmancik et al. 1987a, 1987b). Musculoskeletal Effects. No studies were located regarding musculoskeletal effects in humans following oral exposure to manganese. In young rats, high concentrations of MnCl, in the diet (10,000-20,000 ppm) led to rickets (Svensson et al. 1985, 1987). However, this was found to be due to a phosphate deficiency stemming from precipitation of manganous phosphate (MnPO,) in the intestine, rather than to a direct biological effect of manganese on bone formation. No significant musculoskeletal effects were observed in mice or rats exposed to average oral doses of 810 or 930 mg manganese/kg/day (as MnSO,) for 2 years, respectively (Hejtmancik et al. 1987a, 1987b). Hepatic Effects. No studies were located regarding hepatic effects in humans following oral exposure to manganese. In animals, a variety of histological changes in subcellular organelles (rough and smooth endoplasmic reticulum, Golgi apparatus) were observed in livers of rats exposed to 12 mg manganese/kg/day (as MnCl,) (Wassermann and Wassermann 1977). However, these changes were not considered to be adverse but adaptive, possibly in response 25 2. HEALTH EFFECTS to the increased requirement for manganese excretion in the bile (see Section 2.3.4). No significant hepatic histological changes were observed in mice or rats exposed to average oral doses of 810 or 930 mg manganese/kg/day (as MnSO,) for 2 years, respectively (Hejtmancik et al. 1987a, 1987b). Renal Effects. No studies were located regarding renal effects in humans following oral exposure to manganese. In animals, no significant renal histopathological changes were observed in mice exposed to 140 mg manganese/kg/day (as Mn;0,) in the diet for 90 days (Gray and Laskey 1980), or in rats or mice exposed to average oral doses of 810 or 930 mg manganese/kg/day (as MnSO,) for 2 years, respectively (Hejtmancik et al. 1987a, 1987b). Dermal/Ocular Effects. No studies were located regarding dermal/ocular effects in humans following oral exposure to manganese. In animals, no significant dermal/ocular histopathological changes were observed in mice or rats exposed to average oral doses of 810 or 930 mg manganese/kg/day (as MnSO,) for 2 years, respectively (Hejtmancik et al. 1987a, 1987b). 2.2.2.3 Immunological Effects No studies were located regarding immunological effects in humans or animals following oral exposure to manganese. 2.2.2.4 Neurological Effects Although inhalation exposure to high levels of manganese is known to result in a syndrome of profound neurological effects in humans (see Section 2.2.1.4, above), there is only limited evidence that oral exposure leads to neurological effects in humans. An outbreak of a disease with manganism-like symptoms was reported in a group of six Japanese families (about 25 people) exposed to high levels of manganese in their drinking water (Kawamura et al. 1941). Symptoms that were noted included a mask-like face, muscle rigidity and tremors, and mental disturbance. Five people were severely affected (two died), two were moderately affected, eight were mildly affected, and ten were not affected. These effects were postulated to be due to contamination of the well water with manganese (14 mg/L) that leached from batteries buried near the well. Although many of the symptoms reported were characteristic of manganese toxicity, several aspects of this outbreak suggest that factors in addition to manganese may have contributed to the course of the disease. First, symptoms appeared to develop very quickly. For example, two adults who came to tend the members of one family developed symptoms within 2-3 weeks. Second, the course of the disease was very rapid, progressing in one case from initial symptoms to death in 3 days. Third, all survivors recovered from the symptoms, even before the manganese content of the well had decreased significantly after removal of the batteries. Thus, while there is no doubt these people were exposed to manganese, there is 26 2. HEALTH EFFECTS considerable doubt that all of the features of this outbreak (particularly the deaths) were due to manganese alone. These limitations notwithstanding, this study indicates that manganese ingestion may lead to neurological effects similar to those seen following inhalation exposure. A manganism-like neurological syndrome has been noted in an aboriginal population living on an island near Australia where environmental levels of manganese are high (Kilburn 1987). Symptoms include weakness, abnormal gait, ataxia, muscular hypotonicity, and a fixed emotionless face. Although it seems likely that excess manganese exposure is an etiologic factor in this disease (Cawte et al. 1987), absence of data on dose-response correlations and absence of data from a suitable control group precludes a firm conclusion on the precise role of manganese. Also, it is possible that other factors (besides manganese) may have contributed to the neurological effects, including genetic factors, dietary deficiencies in antioxidants and calcium, and excess alcohol consumption (Cawte et al. 1989). Studies in animals also indicate that low calcium intake may result in neurological damage, perhaps as a result of excess absorption of other dietary metals such as aluminum (Garruto et al. 1989). Also, it should be noted that if manganese intake is a causal factor, exposure of the population could occur not only through the oral route (food, water, soil), but also by inhaling manganese-containing dusts in air, either in the environment or in the workplace (Cawte et al. 1987). More recently, Kondakis et al. (1989) reported that chronic intake of drinking water containing elevated levels of manganese (0.08-2.3 mg/L) led to increased prevalence of neurological signs in elderly residents (average age 67 years) of two small towns in Greece, compared to similar residents in a town where manganese levels were 0.01 mg/L. Over 30 different neurological signs and symptoms were evaluated, each being weighted according to its diagnostic value for Parkinsonism. Based on this system, the average neurological scores for the residents of the control town (0.01 mg/L) and the two towns with elevated manganese (0.08-2.3 mg/L) were 2.7, 3.9, and 5.2, respectively. This study suggests that above-normal oral exposure to manganese might be of health concern, but there are a number of limitations to this study which make this conclusion uncertain. First, no details were reported on which neurological signs or symptoms were increased, so it is difficult to judge if the difference was due to effects characteristic of manganism or to nonspecific parameters. Second, the weighting factors assigned to each neurological sign were largely arbitrary, and it is not clear whether the same results would have been obtained if different weighting factors had been used. Third, many of the parameters included in the scoring were subjective (e.g., weakness, irritability, insomnia, depression, poor memory), and little effort was taken to avoid bias in the examiner or in the study populations. Fourth, as in all ecological studies of this sort, no evidence was obtained to indicate that those individuals who experienced neurological signs did in fact ingest higher levels of manganese than unaffected individuals. Finally, the authors reported that the populations in the towns were very similar to each other, but provided little data to substantiate this. In this regard, even small differences in age, 27 2. HEALTH EFFECTS occupational exposures, or general health status could account for the small differences observed. Thus, this study supports, but does not prove the concept that chronic oral intake of manganese can lead to neurological changes in humans. Other evidence of neurological effects following oral exposure was noted in a case report of a man who mistakenly ingested low doses of potassium permanganate (about 1.8 mg manganese/kg/day) for 4 weeks (Holzgraefe et al. 1986). After several weeks, the man began to notice weakness and impaired mental capacity. Although exposure was stopped after 4 weeks, a syndrome similar to Parkinson's disease developed after about 9 months. Since only one person was involved, it is difficult to be sure the effects (especially the later neurological signs) were causally related to the exposure. Also, the exposure was to MnO,” rather than a compound of Mn+2. The authors speculated that the ingested MnO,” was reduced to Mn+2 or Mn+3, and while this is expected, it was not measured. Since MnO,” is a corrosive agent, it seems likely that MnO,” may have caused significant injury to the gastrointestinal tract (the patient did experience marked stomach pain), perhaps leading to a larger-than-normal gastrointestinal absorption of manganese. For these reasons, this study is not relevant in identifying an oral dose of Mn+2 that leads to neurological effects, and so it is not plotted in Figure 2-2. Considerably more data are available on the neurological effects of manganese ingestion in animals. Only a few studies have reported clinical signs such as weakness, ataxia, or altered gait following oral dosing. For example, Gupta et al. (1980) reported that monkeys given 25 mg manganese/kg/day (as MnCl,) for 18 months developed weakness and muscular rigidity (however, no data were provided to support this). Kristensson et al. (1986) found that rats dosed with 150 mg manganese/kg/day (as MnCl,) developed a rigid and unsteady gait after 2-3 weeks, but this was a transient condition that was not apparent by 7 weeks. Most other studies in animals have only been able to detect alterations in motor activity (hypo- or hyperactivity) or changes in brain neurotransmitter levels. As shown in Table 2-2 and Figure 2-2, changes of this sort have been reported at oral exposure levels of around 10-600 mg manganese/kg/day (as MnCl,) (e.g., Bonilla and Prasad 1984; Chandra 1983; Gray and Laskey 1980; Lai et al. 1984; Nachtman et al. 1986). Studies in neonatal animals have detected biochemical changes at somewhat lower doses (1-10 mg manganese/kg/day) (Chandra and Shukla 1978; Deskin et al. 1980), suggesting that young animals might be more susceptible to manganese than adults. A more thorough discussion of the significance of these studies is presented in Sections 2.4 and 2.7. 2.2.2.5 Developmental Effects The incidence of birth defects has been investigated in a small population of people living on an island where environmental levels of manganese are high (Kilburn 1987), but the data are too limited to judge if the observed incidence is higher than expected. No other studies were located regarding developmental effects in humans or animals following oral exposure to manganese. 28 2. HEALTH EFFECTS 2.2.2.6 Reproductive Effects No studies were located regarding reproductive effects in humans following oral exposure to manganese. However, several intermediate-duration studies in rats and mice indicate that manganese ingestion can lead to delayed maturation of reproductive function in males. The principal effect appears to be decreased testosterone production, which in turn leads to a delayed growth of the male reproductive tract (Gray and Laskey 1980; Laskey et al. 1982, 1985). These effects do not appear to be severe enough to alter sperm morphology (Hejtmancik et al. 1987a, 1987b) or male reproductive function (Laskey et al. 1982) in the adult. This effect is thought to be via a direct action on the Leydig cells, rather than to an alteration in follicle- stimulating hormone or luteinizing hormone levels (Laskey et al. 1985). A slight decrease in pregnancy rate was observed in rats exposed to 3,500 ppm Mn,;0, in the diet for 90-100 days prior to breeding (Laskey et al. 1982). Since both sexes were exposed, it is not possible to conclude whether the effect was in males, females, or both. However, this exposure regimen did not have significant effects on female reproductive parameters such as litter size, ovulations, resorptions, or fetal weights (Laskey et al. 1982). Similarly, Kontur and Fechter (1988) found no significant effect on litter size or weight in female rats exposed to MnCl, in drinking water except at concentrations so high (20,000 mg/L) that water intake by the dams was severely reduced. This suggests that females may not be as sensitive to manganese intake as males. The highest NOAEL values and all reliable LOAEL values for reproductive effects in each species and duration category are recorded in Table 2-2 and plotted in Figure 2-2. 2.2.2.7 Genotoxic Effects No studies were located regarding genotoxic effects in humans following oral exposure to manganese. In male rats, repeated oral doses of 0.014 mg manganese/kg/day (as MnCl,) for 80 days did not produce any significant chromosomal damage either in bone marrow or spermatogonial cells (Dikshith and Chandra 1978). Effects at higher doses were not investigated. Other genotoxicity studies are discussed in Section 2.4. 2.2.2.8 Cancer No studies were located regarding cancer in humans following oral exposure to manganese. Chronic (2-year) feeding studies in rats and mice performed for the NTP have yielded equivocal evidence of a carcinogenic potential. In rats, males exposed to 86, 290, or 930 mg manganese/kg/day (as MnSO,) had an increased incidence of pancreatic cell adenomas and carcinomas (Hejtmancik et al. 1987a). Although the incidence was low and was not dose responsive (4 out of 50 in all three dose groups), the incidence in control males was zero. This tumor type was noted in only one female (in the mid-dose group). No increases in tumor frequency were detected in any other tissues. 29 2. HEALTH EFFECTS In mice, a small increase in the incidence of pituitary adenomas was noted in females but not males exposed to 810 mg manganese/kg/day (as MnSO,) (Hejtmancik et al. 1987b). However, the rate was within historical control rates, and the significance was considered to be equivocal. No increases in tumor frequency were detected in other tissues or at lower doses (81 or 270 mg/kg). These studies are currently undergoing review and validation by NTP (1990). 2.2.3 Dermal Exposure No studies were located regarding the following health effects in humans or animals after dermal exposure to manganese: Death Systemic Effects Immunological Effects Neurological Effects Developmental Effects Reproductive Effects NNN RR NNN www www ans WN RE No No w .7 Genotoxic Effects Genotoxicity studies are discussed in Section 2.4. 2.2.3.8 Cancer No studies were located regarding carcinogenic effects in humans or animals after dermal exposure to manganese. 2.3 TOXICOKINETICS 2.3.1 Absorption 2.3.1.1 Inhalation Exposure No studies were located regarding the amount of manganese that is absorbed by humans or animals following inhalation exposure to manganese dusts. In general, the extent of inhalation absorption is a function of particle size, since this determines the extent and location of particle deposition in the respiratory tract. Particles that are deposited in the lower airway are probably mainly absorbed, while particles deposited in the upper airways may be transported by mucociliary transport to the throat, where they are swallowed into the stomach. This process has been found to account for clearance of a significant fraction of manganese-containing particles initially deposited in the lung (Drown et al. 1986; Mena et al. 1969). Thus, manganese may be absorbed both from the lungs and in the gastrointestinal tract following inhalation of manganese dust. However, the relative amounts absorbed from each site are not known. 30 2. HEALTH EFFECTS 2.3.1.2 Oral Exposure The amount of manganese absorbed across the gastrointestinal tract in humans is rather variable, but typically averages about 3%-5% (Davidsson et al. 1988, 1989; Mena et al. 1969). Data were not located on the relative absorption fraction for different manganese compounds, but there does not appear to be a marked difference between retention of manganese ingested in food (5% at day 10) or water (2.9% at day 10) (Davidsson et al. 1988, 1989). One of the key determinants of absorption appears to be dietary iron intake, with low iron levels leading to increased manganese absorption (Mena et al. 1969). This is probably because both iron and manganese are absorbed by the same transport system in the gut. The activity of this system is inversely regulated by dietary iron and manganese intake levels (Chandra and Tandon 1973; Diez-Ewald et al. 1968; Rehnberg et al. 1982; Thomson et al. 1971). Studies of oral absorption of manganese in animals have yielded results that are generally similar to those in humans. Gastrointestinal uptake of MnCl, in rats has been estimated to be 2.5%-5.5% (Pollack et al. 1965). Uptake is increased by iron deficiency (Pollack et al. 1965) and decreased by pre-exposure to high dietary levels of manganese (Abrams et al. 1976a). In addition, several studies in animals indicate that gastrointestinal absorption may vary with age. For example, Rehnberg et al. (1980, 1981) noted that exposure of rats to manganese tetroxide in food or water resulted in much larger increases in tissue levels in neonatal rats (age 1-15 days) than in older rats. This was judged to be due to a greater absorption in neonates as a result of slower rate of transport through the gut (Rehnberg et al. 1985). Similar results have been reported in rats exposed to MnCl, (Kostial et al. 1978). However, such age-dependent differences in tissue retention of manganese could also be due to differences in excretory ability (e.g., Miller et al. 1975), or to age-related changes in dietary intake levels of iron and manganese (Ballatori et al. 1987). 2.3.1.3 Dermal Exposure No studies were located regarding absorption in humans or animals after dermal exposure to manganese. It is generally considered that uptake across intact skin is very limited for most inorganic metal ions. 2.3.2 Distribution Manganese is a normal component of human and animal tissues and fluids. In humans, most tissue concentrations range between 0.1 and 1 pg manganese/g wet weight (Sumino et al. 1975; Tipton and Cook 1963), with highest levels in liver, pancreas, and kidney, and lowest levels in bone and fat (Table 2-3). Levels of manganese in fetal tissues are similar to adult (Widdowson et al. 1972). Levels in tissues from animals fed a normal diet are generally 31 2. HEALTH EFFECTS TABLE 2-3. Normal Manganese Levels in Human and Animal Tissues Tissue concentrations Mn wet weight Humans Rats Rabbits Tipton Sumino Rehnberg Fore and and Cook et al. et al. Morton Tissue (1963) (1975) (1982) (1952) Liver 1.68 1.2 2.6-2.9 2.1 Pancreas 1.21 0.77 No data 1.6 Adrenals 0.20 0.69 2.9 0.67 Kidney 0.93 0.56 0.9-1.0 1.2 Brain 0.34 0.30% 0.4 0.36 Lung 0.34 0.22 No data 0.01 Heart 0.23 0.21 No data 0.28 Testes 0.19 0.20 0.4 0.36 Ovary 0.19 0.19 No data 0.60 Muscle 0.09 0.09 No data 0.13 Spleen 0.22 0.08 0.3 0.22 Fat No data 0.07 No data No data Bone (rib) No data 0.06 No data No data Pituitary No data No data 0.5 2.4 Average of cerebrum and cerebellum 32 2. HEALTH EFFECTS similar, but perhaps slightly higher, than those in humans (Fore and Morton 1952; Rehnberg et al. 1982). Levels of manganese in the milk of rats fed a normal diet averaged 0.054 ug/g (Miller et al. 1975). Data on changes in tissue levels following acute exposures to excess manganese are presented below. 2.3.2.1 Inhalation Exposure For short durations following inhalation exposure of mice to manganese dust, the concentration of manganese in lung is approximately proportional to the concentration of manganese in air (Adkins et al. 1980c). However, as noted earlier, the main fate of particles that are deposited in the lung is transport to the gastrointestinal tract (Mena et al. 1969). The rate of particle transport from the lungs has not been quantified in humans, but half-times in animals range from 3 hours to 1 day (Adkins et al. 1980c; Bergstrom 1977). The relative increases in tissue levels of manganese following inhalation exposure has not been thoroughly investigated. Increases of 20-60% in manganese levels in kidney and spleen were noted in mice 24-48 hours after exposure to MnO, (Adkins et al. 1980c). Preferential accumulation of manganese in specific locations in the brain (including the caudate nucleus, globus pallidus and the substantia nigra) was noted in a monkey exposed to an aerosol of MnCl, (20-40 mg/m’) several hours per day for 3-5 months (Newland et al. 1989). This preferential uptake could play a role in the characteristic neurological effects of manganese (see Section 2.4). 2.3.2.2 Oral Exposure Studies in animals indicate that oral exposure to manganese compounds results in increased manganese levels in all tissue, but that the magnitude of the increase diminishes over time (Kristensson et al. 1986; Rehnberg et al. 1980, 1981, 1982). Table 2-4 provides illustrative data, based on rats exposed to 3,500 ppm manganese in the diet (as Mn;0,) for up to 224 days. As the data reveal, large increases in tissue levels compared to controls occurred in all tissues over the first 24 days, but levels tended to decrease toward control as exposure was continued. This is thought to be due to a homeostatic mechanism that leads to decreased absorption and/or increased excretion of manganese when manganese intake levels are high (Abrams et al. 1976a; Ballatori et al. 1987; Mena et al. 1967). 2.3.2.3 Dermal Exposure No studies were located regarding tissue distribution of manganese in humans or animals following dermal exposure to manganese. 33 2. HEALTH EFFECTS TABLE 2-4. Tissue Levels in Rats After Oral Exposure to Manganese? Tissue concentration (% control)? Tissue 24 days 60 days 224 days Liver 810 137 138 Kidney 430 102 128 Brain 540 175 125 Testes 260 125 100 Adapted from Rehnberg et al. (1982) bValues presented are the ratio (expressed as a percentage) of tissue levels in animals receiving 3,550 ppm manganese in the diet (as Mn,0,) compared to animals receiving a normal diet (50 ppm). 34 2. HEALTH EFFECTS 2.3.3 Metabolism Manganese is capable of existing in a number of oxidation states, and limited data suggest that manganese may undergo changes in valence within the body. Circumstantial support for this hypothesis comes from the observation that the valence of the manganese ion in several enzymes appears to be +3 (Leach and Lilburn 1978; Utter 1976), while most manganese intake from the environment is either as +2 or +4 (see Chapter 5). Another line of evidence is based on measurements of manganese in tissues and fluids using electron spin resonance (ESR), which detects only the +2 oxidation state of manganese. When animals were injected with MnCl,, levels of manganese increased in bile and tissues, but only a small portion of this was in a form that gave an ESR signal (Sakurai et al. 1985; Tichy and Cikrt 1972). This suggests that Mn(+2) is converted to another valence (probably Mn+3), but it is also possible that formation of complexes between Mn(+2) and biological molecules (bile salts, proteins, nucleotides, etc.) results in loss of the ESR signal without formal oxidation of the manganese ion. Gibbons et al. (1976) observed that human ceruloplasmin led to the oxidation of Mn(+2) to Mn(+3) in vitro. Although this was not studied in vivo, this is a likely mechanism for manganese oxidation in blood. These workers also noted that manganese oxidation led to a shift in manganese binding in vitro from a,-macroglobulin to transferrin, and that in vivo clearance of Mn(+2)-a,-macroglobulin from cows was much more rapid than clearance of Mn(+3)-transferrin (Gibbons et al. 1976). This suggests that the rate and extent of manganese reduction/oxidation reactions may be important determinants of manganese retention in the body. 2.3.4 Excretion 2.3.4.1 Inhalation Exposure Humans who inhaled either MnCl, or Mn,0, excreted about 60% of the material originally deposited in the lung in the feces within 4 days (Mena et al. 1969). Similarly, rats exposed to either MnCl, or Mn,0, by intratracheal instillation excreted about 50% of the dose in the feces within 3-7 days (Drown et al. 1986). Monkeys exposed to an aerosol of MnCl, excreted most of the manganese with a half-time of 0.4-0.9 days (Newland et al. 1987). However, a portion of the label was retained in the lung and brain, probably within cells or bound to manganese-containing proteins. Clearance of this label was slower, occurring with half-times of 12-250 days. These data do not provide information on how much of the manganese excreted in the feces after inhalation exposure was first absorbed and then excreted via the bile, and how much was simply transported directly from the lung to the gastrointestinal tract without absorption. 35 2. HEALTH EFFECTS 2.3.4.2 Oral Exposure Humans ingesting tracer levels of radioactive manganese (usually as MnCl,) excreted the manganese with whole-body retention half-times of 13-37 days (Davidsson et al. 1989; Mena et al. 1969; Sandstrom et al. 1986). The route of manganese loss was not documented, but was presumably mainly fecal following biliary excretion. 2.3.4.3 Dermal Exposure No studies were located regarding excretion of manganese in humans or animals following dermal exposure to manganese. 2.3.4.4 Other Routes of Exposure Rats exposed to MnCl, by intravenous injection excreted 50% of the dose in the feces within 1 day (Klaassen 1974) and 85% by day 23 (Dastur et al. 1971), indicating that biliary excretion is the main route of manganese clearance. Only minimal levels were excreted in urine (less than 0.1% of the dose within 5 days) (Klaassen 1974). Direct measurement of manganese levels in bile revealed concentrations up to 150-fold higher than in plasma, indicating the existence of either an active transport system (Klaassen 1974) or some sort of trapping mechanism (Tichy and Cikrt 1972). Based on the difference in blood levels following portal or femoral injection, Thompson and Klaassen (1982) estimated that about one-third of the manganese burden in blood is removed in each pass through the liver. Some manganese apparently can cross directly from the blood to the bile (Bertinchamps et al. 1965; Thompson and Klaassen 1982), but most appears to be secreted into the bile via the liver (Bertinchamps et al. 1965). The chemical state of manganese in bile is not known, but a considerable fraction exists in some sort of bound or complexed form (Tichy and Cikrt 1972). This material is apparently subject to enterohepatic recirculation, since biliary manganese is reabsorbed from intestine more efficiently than free Mn(+2) (Klaassen 1974). The significance of this recirculation is not known. While biliary secretion appears to be the main pathway by which manganese is excreted into the intestines, direct transport from blood across the intestinal wall may also occur (Bertinchamps et al. 1965; Garcia-Aranda et al. 1983, 1984). The relative amount of total excretion attributable to this pathway has not been quantified, but it appears to be only a fraction of that attributable to biliary secretion (Bertinchamps et al. 1965). 2.4 RELEVANCE TO PUBLIC HEALTH Manganese is a naturally-occurring element that exists in the environment primarily as salts or oxides of Mn(+2) or Mn(+4). There is no direct evidence that manganese is beneficial or essential in humans, but ingestion of manganese compounds is known to be required for good health in 36 2. HEALTH EFFECTS animals (Cotzias 1958; Leach and Lilburn 1978; Underwood 1971). Effects that have been associated with manganese deficiency include impaired growth (Bolze et al. 1985; Smith et al. 1944), skeletal abnormalities (Amdur et al. 1944), impaired reproductive function in females and testicular degeneration in males (Boyer et al. 1942; Waddell et al. 1931), ataxia (Hurley et al. 1961), and altered metabolism of carbohydrates (Baly et al. 1988; Hurley et al. 1984) and lipids (Abrams et al. 1976a). The precise biochemical basis of this nutritional requirement in animals is not known, but a number of enzymes appear to require manganese for their proper function (Leach and Lilburn 1978; Utter 1976). Based on the studies in animals, it is presumed that humans also require manganese for good health, even though no cases of manganese deficiency have been observed in humans (Schroeder et al. 1966; Underwood 1971). The recommended daily intake of manganese is 2.5-5 mg/day for an adult (NAS 1980b). This is about the same dose as is usually delivered via the diet, although individual intakes may be higher or lower (see Section 5.5). While manganese is beneficial or essential at low intake levels, inhalation or oral exposure to high levels can cause adverse effects. As discussed in Section 2.2.1, the most sensitive and most significant effect caused by inhalation exposure to manganese dusts in air is neurological injury. Effects may sometimes occur after exposures of only several months (Rodier 1955), but quantitative data are not available to derive either acute- or intermediate-duration inhalation MRLs. For chronic inhalation exposure, Iregren (1990) reported that persons exposed to a median concentration of 0.14 mg/m’ of manganese dust for 1-35 years had below-average scores in a number of neurobehavioral tests, such as reaction time and finger tapping. Based on this LOAEL, a chronic inhalation MRL of 0.0003 mg manganese/m’ (0.3 pg manganese/m’) was derived using an uncertainty factor of 100 (10 for use of a LOAEL and 10 for human variability), and using factors of 5/7 and 8/24 to account for intermittent exposure (5 days/week, 8 hours/day). The study by Iregren (1990) is supported by the data of Roels et al. (1987a), who noted decreased performance in comparable neurobehavioral tests along with an increased incidence of weakness and decreased hand steadiness in workers chronically exposed to 1 mg/m® of manganese dusts. Data on the effects of manganese following oral exposure are less extensive. Neurological effects similar to those seen after inhalation exposure have been reported by several researchers (e.g., Holzgraefe et al. 1986; Kawamura et al. 1941; Kilburn 1987; Kondakis et al. 1990). However, in each case there is uncertainty regarding the exposure level or whether the effects were solely attributable to manganese, so these studies are not suitable for the derivation of oral MRL values. Dermal MRL values were not derived for manganese because dermal absorption of manganese is not believed to be toxicologically significant, and because there is currently no appropriate methodology for development of dermal MRLs. More detailed information on the adverse effects of inhalation and oral exposure to manganese is presented below. 37 2. HEALTH EFFECTS Death. No cases of death in humans or animals have been reported following inhalation exposure to manganese. There is one report of two people who died after ingesting manganese-contaminated well-water (Kawamura et al. 1941), but there is considerable doubt that the deaths were due to the manganese (see Section 2.2.2.4). Oral administration of highly concentrated manganese solutions (16,000-44,000 mg manganese/L) can cause lethality in animals (Kostial et al. 1978; Rehnberg et al. 1980; Smyth et al. 1969), but ingestion of manganese in food or water has not been reported to cause mortality in animals. These findings indicate that manganese has low acute toxicity by both the oral and inhalation routes, and death is not expected to result from exposures likely to be encountered in the environment or near waste sites. Systemic Effects. Most studies in humans and animals indicate that manganese exposure does not cause significant injury to heart, stomach, blood, muscle, bone, liver, kidney, skin, or eyes (Hejtmancik et al. 1987a, 1987b; Shiotsuka 1984; Ulrich et al. 1979b). However, if manganese is in the Mn(+7) valence state (as in potassium permanganate), then ingestion or dermal contact may lead to severe corrosion at the point of contact (Southwood et al. 1987). Respiratory Effects. Inhalation exposure to manganese dusts often leads to an inflammatory response in lung in both humans and animals. This generally leads to increased incidence of cough and bronchitis (Lloyd Davies 1946; Roels et al. 1987a; WHO 1987), and can lead to mild to moderate injury to lung tissue (Lloyd Davies 1946; Shiotsuka 1984; Suzuki et al. 1978; Zaidi et al. 1973), along with minor decreases in lung function (Roels et al. 1987a). In addition, susceptibility to infectious lung disease may be increased (Adkins et al. 1980b; Maigetter et al. 1976), leading to increased pneumonitis and pneumonia in some manganese-exposed worker populations (Lloyd Davies 1946; Lloyd Davies and Harding 1949). These effects have been reported primarily in workers exposed to fairly high concentrations of manganese dusts in the workplace, although there are some data that residents near ferromanganese factories may also have an increased prevalence of respiratory effects (WHO 1987). The risk of lung injury in people exposed to the levels of manganese typically found in the general environment is expected to be quite low (EPA 1985d). It should be noted that these effects on the lung are not unique to manganese-containing dusts but are produced by a variety of inhalable particulate matter (EPA 1982). On this basis, it seems most appropriate to evaluate the risk of inflammatory effects on the lung in terms of total suspended particulate matter (TSP) or particulate matter smaller than 10 pm in diameter (PM;,), rather than in terms of the concentration of manganese in air (EPA 1985d). Immunological Effects. No studies were located regarding immunological effects in humans or animals following inhalation or oral exposure to manganese. However, studies in animals exposed to MnCl, by intraperitoneal or intramuscular injection indicate that manganese can influence several immunological cell types. For example, manganese treatment stimulates 38 2. HEALTH EFFECTS macrophage and natural killer cell activity in mice, probably by increased productions of interferon (Rogers et al. 1983; Smialowicz et al. 1985, 1987). Manganese also alters the responsiveness of lymphoid cells to mitogens and inhibits antibody production in response to a T-dependent antigen (Hart 1978; Lawrence 1981; Srisuchart et al. 1987). It is difficult to judge whether these manganese-dependent modulations in immune cell activity are likely to result in clinically significant impairment of the immune function in exposed humans, but this is an area of potential concern. Studies in animals indicate that impaired immune function is not responsible for the increased sensitivity to lung infection discussed above (Adkins et al. 1980c). Neurological Effects. There is clear evidence from studies of humans exposed to manganese dusts in mines and factories that inhalation of manganese can lead to a series of serious and ultimately disabling neurological effects (Emara et al. 1971; Rodier 1955; Saric et al. 1977; Schuler et al. 1957). This disease, termed manganism, typically begins with feelings of weakness and lethargy. As the disease progresses, a number of neurological signs may become manifest. Although not all individuals develop identical signs, the most common are a slow and clumsy gait, speech disturbances, a mask-like face, and tremor. These effects are largely irreversible, persisting for many years after exposure ceases (Cotzias et al. 1968). In addition, a syndrome of psychological disturbances (hallucination, psychosis) frequently emerges, although such symptoms are sometimes absent (e.g., Cook et al. 1974). Ultimately the patient develops severe hypertonia and muscle rigidity, and may be completely and permanently disabled (Rodier 1955). Studies in animals exposed to manganese dusts (usually MnO,) have sometimes revealed biochemical or neurobehavioral evidence of neurological effects (Bird et al. 1984; Chandra and Shukla 1978; Deskin et al. 1980; Lown et al. 1984; Morganti et al. 1985), although signs of impaired motor function similar to those seen in humans are usually not detected. These data indicate that animals (especially rodent species) are not good models for the neurological effects of inhaled manganese in humans, at least with respect to defining quantitative dose-response relationships. The basis for this difference in susceptibility is not known. However, monkeys exposed to doses as low as 5 mg/kg of manganese (as MnCl,) by intravenous injection showed a partially reversible impairment of a conditioned response, and cumulative doses of 40 mg/kg or higher produced action tremor (Newland and Weiss 1992). The tremor was irreversible in two of three animals. Onset of these behavioral effects corresponded with an increase in the manganese content of the global pallidus and the substantia nigra. This study confirms that nonhuman primates can develop neurological and neurobehavioral injuries somewhat similar to those in humans, even if the exposure thresholds leading to effects are somewhat different. One of the striking aspects of manganism is its similarity to Parkinson's disease (Cotzias 1958; Mena et al. 1974), although there are some distinctions (Barbeau 1984). Parkinson's disease is believed to be due to the selective loss of a group of subcortical neurons whose cell bodies lie in the substantia nigra and whose axons terminate in the basal ganglia (which 39 2. HEALTH EFFECTS includes the caudate nucleus, the putamen, the globus pallidus, and other structures). These nigral neurons utilize dopamine as their neurotransmitter, and treatment of Parkinson patients with levo-dopa (the metabolic precursor to dopamine) often relieves some of the symptoms of Parkinson's disease (Bernheimer et al. 1973). In a similar fashion, neuropathological changes are detectable in the basal ganglia of humans with manganism, although the specific area of injury appears to be primarily in the globus pallidus rather than the substantia nigra (Yamada et al. 1986). In addition, limited evidence suggests that levels of dopamine in the caudate nucleus and putamen are decreased in patients with manganism (Bernheimer et al. 1973), and administration of levo-dopa alleviates some of the symptoms of manganism (Barbeau 1984; Huang et al. 1989). The precise biochemical mechanism by which manganese leads to this selective destruction of dopaminergic neurons is not known, but many researchers believe that manganese ion (Mn+2) enhances the oxidation or turnover of various intracellular catecholamines, leading to increased production of free radicals, reactive oxygen species, and other cytotoxic metabolites, along with a depletion of cellular antioxidant defense mechanisms (Barbeau 1984; Donaldson 1987; Garner and Nachtman 1989; Graham 1984; Halliwell 1984; Parenti et al. 1988). It is important to note that oxidation of catechols is more efficient with the trivalent species (Mn+3) than the divalent (Mn+2) or tetravalent (Mn+4) species (Archibald and Tyree 1987). Formation of Mn(+3) may occur by oxidation of Mn(+2) by superoxide (0,7). In cases where exposure is to Mn(+7), it is likely that reduction to the Mn(+2) or Mn(+3) state occurs (Holzgraefe et al. 1986), but this has not been demonstrated. Reliable dose-response data on the inhalation exposure levels leading to neurological injury in humans are not extensive, but recent epidemiological data indicate that a median workplace exposure of 0.14 mg/m® may produce preclinical signs of neurological change in some people (Iregren 1990). Selecting this value as a LOAEL, a chronic inhalation MRL of 0.0003 mg/m? (0.3 ug manganese /m?>) has been derived, as described in footnote c in Table 2-1. Since typical ambient air concentrations of manganese range from 0.005 to 0.14 ug/m® (see Section 5.4), it is judged that neurological injury is not likely to be of concern from normal environmental inhalation exposures. While manganism is clearly associated with chronic inhalation exposure to high levels of manganese, there is only limited evidence that oral exposure is of concern. There are a few reports of manganism-like symptoms in people who ingested unusually high levels of manganese, but all of these reports have limitations that make data interpretation difficult. For example, Kawamura et al. (1941) reported an outbreak of a disease in a small group of people exposed to approximately 14 mg/L of manganese in their drinking water (corresponding to a dose of about 0.5 mg manganese/kg/day). While many of the symptoms were similar to those associated with inhalation exposure, there were a number of aspects of the incident which suggest that manganese was not solely responsible (see Section 2.2.2.4). In a more recent study, Kondakis et al. (1989) reported an increased prevalence of neurological signs in the 40 2. HEALTH EFFECTS elderly residents of two towns in Greece where drinking water contained elevated levels of manganese (0.2-2 mg/L, corresponding to doses of up to about 0.06 mg manganese/kg/day). However, the individual signs that were monitored were mostly nonspecific, and no details were provided on which signs were more prevalent in the exposed areas. Therefore, it is difficult to be certain that manganese was the causative agent. In another report, = (Holzgraefe et al. 1986), one man who accidentally ingested KMnO, for several months later developed some manganism-like symptoms. However, since only one person was involved and since absorption may have been markedly increased by direct damage to the stomach, it is difficult to draw conclusions regarding the neurological risks from ingestion of Mn(+2) compounds. Several studies have found that manganese levels in hair are higher in learning disabled children than in normal children (Collipp et al. 1983; Pihl and Parkes 1977). The route of excess exposure is not known, but is presumably mainly oral. These observations are consistent with the possibility that excess manganese ingestion could lead to learning or behavioral impairment in children. However, an association of this sort is not sufficient to establish a cause- effect relationship, since a number of other agents, including lead, might also be involved (Pihl and Parkes 1977). Despite the limitations of these studies, the similarity of the effects seen in these cases of oral exposure compared to those associated with inhalation exposure suggest that excess manganese intake by humans might lead to neurological injury, even if only under special (and not yet understood) conditions. Studies in animals exposed to manganese by the oral route have revealed biochemical changes in various neurotransmitter levels, especially in the region of the basal ganglia (Bonilla and Prasad 1984; Chandra 1983; Eriksson et al. 1987a; Gianutsos and Murray 1982), and occasional evidence of neurological impairment has been observed as altered behavior (Chandra 1983; Gray and Laskey 1980) or minor motor dysfunction (Gupta et al. 1980; Kristensson et al. 1986). Although animals exposed to manganese generally do not develop the striking bradykinesia, ataxia, and hypertonicity characteristic of manganism in humans, the effects in animals are at least qualitatively similar to the biochemical and functional changes in humans exposed by the inhalation route. In adult animals, these effects are usually seen at doses of 40-400 mg manganese/kg/day (see Table 2-2), although Bonilla and Prasad (1984) noted an effect in rats exposed to 14 mg/kg/day. Taking a dose of 14 mg manganese/kg/day as the LOAEL for these changes (which do not appear to be associated with any visible dysfunction), this would correspond to a dose of about 980 mg/day in an adult human. Since typical dietary intake via food provides about 4 mg/day (see Section 5.5), environmental levels would have to be very high to yield an intake level that would approach this dose. However, several studies in the neonatal rats indicate biochemical changes in the brain may be produced by doses of 1-10 mg manganese/kg/day (Chandra and Shukla 1978; Deskin et al. 1980). Taking 1 mg/kg/day as the LOAEL in neonates, the corresponding dose in a human infant (5-10 kg) would be 5-10 mg/day. Although no data are available on manganese intake by infants, levels in milk (0.02-0.49 ppm) and infant foods (0.17-4.83 ppm) (see 41 2. HEALTH EFFECTS Table 5-3) are sufficiently low that doses would not approach this level. While these data from animals suggest that typical human exposure levels are not of concern to either adults or infants, it must be remembered that animals do not appear to be as sensitive to manganese as humans. Thus, there is considerable uncertainty in using these animal data to estimate a no-effect oral eXposure level in humans or to evaluate the potential for adverse effects in humans exposed near a waste site. Developmental Effects. The effects of manganese on fetal development have not been thoroughly investigated. The incidence of stillbirths and malformations has been studied in an Australian aboriginal population living on an island where environmental levels of manganese are high (Kilburn 1987). However, data from a suitable control group are lacking and the study population is so small that it is not possible to judge if the incidence of developmental abnormalities is higher than average. Data from animals are also sparse. The offspring of rats exposed to high levels of manganese dust in air during gestation weighed less than average, and they were less active than normal (Lown et al. 1984). This effect on activity, which persisted into adulthood, suggests that manganese exposure might be causing neurological effects in utero. Intraperitoneal injection of pregnant mice with 12.5 mg manganese/kg (as MnSO,) on days 8-10 of gestation resulted in exencephaly and embryolethality (Hebseor and Valois 1987), confirming that adverse developmental effects may occur if maternal exposure to manganese is high enough. However, it is not possible to draw conclusions about oral or inhalation exposure levels that might be fetotoxic from these data, due to the marked toxicokinetic differences in rate and extent of absorption expected between parenteral and nonparenteral exposures. Taken together, the studies from humans and animals suggest that high levels of manganese intake might lead to developmental effects, but the data are too limited to draw firm conclusions. Reproductive Effects. Decreased libido and impotence are frequently observed in male workers exposed to high levels of manganese dusts in the workplace (Emara et al. 1971; Mena et al. 1967; Rodier 1955), and the number of children born to occupationally exposed males may be lower than average (Lauwreys et al. 1985). It seems likely that these effects are at least partly neurological in origin, but there is also evidence from studies in animals that manganese can damage the testes. In young male animals (rats and mice) exposed to manganese orally, growth and maturation of the testes and other reproductive tissues was delayed (Gray and Laskey 1980), probably because of decreased testosterone secretion by Leydig cells (Laskey et al. 1982, 1985). However sperm counts and morphology do not appear to be affected (Hejtmancik et al. 1987a, 1987b; Laskey et al. 1982). A much more striking effect has been reported in rabbits exposed to manganese by intratracheal instillation (Chandra et al. 1973; Seth et al. 1973). A single dose of 160 mg manganese/kg (as MnO,) resulted in a slow degeneration of the seminiferous tubules over a period of 1-8 months. This was associated with loss of spermatogenesis and complete infertility (Chandra et al. 1975; Seth et al. 1973). Similar degenerative changes in testes have been reported in rats and 42 2. HEALTH EFFECTS mice following intraperitoneal injection of MnSO, (Chandra et al. 1975; Singh et al. 1974) and in rabbits following intravenous injection of MnCl, (Imam and Chandra 1975). It is not clear why testicular damage is more severe in some cases than in others, but could be due to toxicokinetic differences between oral and parenteral exposures. Although direct damage to the testes has not been reported in humans following manganese exposure, specific studies to investigate this have not been reported. The observations from animal studies suggest this might be of concern. Information on reproductive effects in females is very limited. Female rats exposed to MnO, by inhalation for 18 weeks had an increased number of pups per litter, perhaps as the result of the beneficial effects of manganese (Lown et al. 1984). No effects on litter size, ovulations, resorptions, or fetal deaths were detected in rats exposed to Mn;0, in the diet (Laskey et al. 1982). These negative findings suggest that reproductive function in females may be less sensitive to manganese than in males, but the data are too sparse to draw firm conclusions. Consequently, risk of reproductive effects in human females exposed near waste sites cannot be evaluated. Genotoxic Effects. The genotoxic effects of manganese (as MnCl, or MnSO,) have been studied in several test systems. Results in vitro (Table 2-5) have been mixed, while results in vivo (Table 2-6) have been negative. It is well established that Mn(+2) can substitute for the magnesium ion (Mg+2) in DNA polymerase in vitro, leading to errors in the fidelity of DNA replication (El-Deiry et al. 1984), but whether this occurs inside intact cells is not known. On balance, these studies indicate that manganese may have genotoxic potential but the data do not permit an evaluation of the genotoxic risk of excess manganese to humans. Cancer. Information on the carcinogenic potential of manganese is limited, and the results are difficult to interpret with certainty. Inhalation exposure of humans to manganese dusts has not been identified as a risk factor for lung cancer, although intraperitoneal injection of mice with MnSO, led to an increased incidence of lung tumors (Stoner et al. 1976). Preliminary data from an NTP study indicate that chronic oral exposure of rats to MnSO, may lead to increased incidence of pancreatic tumors (adenomas plus carcinomas), but this effect was quite small and was not dose-responsive (Hejtmancik et al. 1987a). In mice, chronic oral exposure to MnSO, resulted in a small increase in pituitary adenomas in females, but the incidence was within historical control values, and this finding was considered equivocal (Hejtmancik et al. 1987b). Repeated intramuscular injection of rats and mice with suspensions of metallic manganese or MnO, did not result in tumors at the injection site or elsewhere (Furst 1978). These data are not adequate to reach a firm conclusion regarding the carcinogenicity of manganese, but suggest that the potential for carcinogenic effects in humans is probably small. TABLE 2-5. Genotoxicity of Manganese In Vitro Results With Without Species (test system) Compound End point Strain activation activation Reference Prokaryotic organisms: Salmonella typhimurium MnCl, Gene mutation TA98 i - Wong 1988 (plate incorporation TA102 - - assay) TA1535 - - TA1537 = Photobacterium fischeri MnCl, Gene mutation P£-13 No data + Ulitzur and (bioluminescence test) (restored (dark mutant) Barak 1988 luminecence) Escherichia coli MnCl, Gene mutation KMBL 3835 No data + Zakour and Glickman 1984 Bacteriophage MnSO, Gene mutation T4 No data + Orgel and Orgel (E. coli lysis) 1965 Bacillus subtilis MnCl, Inhibition of growth M45 No data + Nishioka 1975 (recombination assay) Mn(NO;), in recombination (Rec™) + MnSO, deficient mutant (Rec”) + Mn (CH,C00), compared to wild KMnO, type (Rec’) = B. subtilis MnCl, Inhibition of growth M45 No data - Kanematsu (recombination assay) Mn(NO;), in recombination (Rec™) ~ et al. 1980 Mn (CH,C00), deficient mutant (Rec”) - compared to wild type (Rec’) Eukaryotic organisms: Fungi: Saccharomeyces cerevisiae MnSO, Gene conversion, D7 No data (+) Singh 1984 reverse mutation Mammalian cells: Mouse lymphoma cells MnCl, Gene mutation L5178Y TK+/- No data + Oberley et al. 1982 Syrian hamster MnCl, Enhancement of No data + Casto embryo cells SA7 transformation et al. 1979 + = positive result; - = negative result; (+) = weakly positive result; KMnO, = potassium permanganate; MnCl, = manganous chloride; MnSO, = manganous sulfate; Mn(NO;), = manganous nitrate; Mn(CH,CO0), = manganous acetate; Rec = recombination C S10d4dd4d HITIVAH ££ TABLE 2-6. Genotoxicity of Manganese In Vivo Exposure Species (test system) Compound End point route Results Reference Nonmammalian systems: Drosophila melanogaster MnSO, Sex-linked Feeding - Valencia recessive lethal Injection - et al. 1986 Drosophila melanogaster MnCl, Somatic mutation Soaking - Rasmuson 1985 larvae Mammalian systems: Albino rat MnCl, Chromosomal Oral Dikshith and (bone marrow cells) aberrations - Chandra 1978 (spermatogonial cells) - = negative result; MnSO, = manganous sulfate; MnCl, = manganous chloride C SIOd4ddd HITVHH VA 45 2. HEALTH EFFECTS 2.5 BIOMARKERS OF EXPOSURE AND EFFECT Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have been classified as markers of exposure, markers of effect, and markers of susceptibility (NAS/NRC 1989). A biomarker of exposure is a xenobiotic substance or its metabolite(s) or the product of an interaction between a xenobiotic agent and some target molecule(s) or cell(s) that is measured within a compartment of an organism (NAS/NRC 1989). The preferred biomarkers of exposure are generally the substance itself or substance-specific metabolites in readily obtainable body fluids or excreta. However, several factors can confound the use and interpretation of biomarkers of exposure. The body burden of a substance may be the result of exposures from more than one source. The substance being measured may be a metabolite of another xenobiotic substance (e.g., high urinary levels of phenol can result from exposure to several different aromatic compounds). Depending on the properties of the substance (e.g., biologic half-life) and environmental conditions (e.g., duration and route of exposure), the substance and all of its metabolites may have left the body by the time biologic samples can be taken. It may be difficult to identify individuals exposed to hazardous substances that are commonly found in body tissues and fluids (e.g., essential mineral nutrients such as copper, zinc, and selenium). Biomarkers of exposure to manganese are discussed in Section 2.5.1. Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within an organism that, depending on magnitude, can be recognized as an established or potential health impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals of tissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital epithelial cells), as well physiologic signs of dysfunction such as increased blood pressure or decreased lung capacity. Note that these markers are often not substance specific. They also may not be directly adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effects caused by manganese are discussed in Section 2.5.2. A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism’s ability to respond to the challenge of exposure to a specific xenobiotic substance. It can be an intrinsic genetic or other characteristic or a preexisting disease that results in an increase in absorbed dose, biologically effective dose, or target tissue response. If biomarkers of susceptibility exist, they are discussed in Section 2.7, "POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE." 2.5.1 Biomarkers Used to Identify and/or Quantify Exposure to Manganese Manganese can be measured with good sensitivity in biological fluids and tissues (see Section 6.1), and levels in blood, urine, and feces have been investigated as possible biomarkers of exposure. Workers exposed to a mean 46 2. HEALTH EFFECTS concentration of 1 mg manganese/m> had higher levels of manganese in blood and urine than unexposed controls (Roels et al. 1987b). Average levels in blood appeared to be related to manganese body burden, while average urinary excretion levels were judged to be most indicative of recent exposures. However, on an individual basis, there was no correlation between the level of workplace exposure and the levels in blood or urine (Roels et al. 1987b; Smyth et al. 1973). Similarly, there was no significant correlation between occupational exposure to manganese and fecal excretion (Valentin and Schiele 1983). These data indicate that manganese in blood, urine, or feces may be useful in detecting groups with above average exposure, but the variability is so great that even relatively large additional exposures are difficult to detect in individuals. In addition to individual variability, another factor that limits the usefulness of measuring manganese in blood, urine, or feces is the relatively rapid rate of manganese clearance from the body. As discussed in Section 2.3, excess manganese in blood is rapidly removed by the liver and excreted into the bile, with very little excretion in urine (Klaassen 1974). Thus, levels of manganese in blood or urine are not expected to be especially sensitive indicators of exposure. Levels in feces could be useful in evaluating relatively recent high-level exposures, but would not be expected to be helpful in detecting chronic low-level exposures. While it is well established that exposure to excess manganese can result in increased tissue levels in animals, the correlation between exposure levels, tissue burdens, and health effects has not been thoroughly investigated in humans. As noted by Rehnberg et al. (1982), manganese levels in tissues are subject to homeostatic regulation via changes in absorption and/or excretion rates. While exposure to very high levels may overwhelm these mechanisms, continuous exposure to moderate excesses of manganese does not cause a continuous increase in tissue levels (Rehnberg et al. 1982). Moreover, even if tissue levels are increased in response to above-average exposure, levels are likely to decrease toward normal after exposure ceases. For example, the level of manganese in the brain of an ex-miner with severe manganism was not different from normal (Yamada et al. 1986). For these reasons, measurement of tissue levels of manganese at autopsy or possibly biopsy may be of some value in detecting current exposure levels, but are not useful in detecting past exposures. In addition, evaluation of manganese exposure by analysis of tissue levels is not readily applicable to living persons except through the collection of biopsy samples. Scalp hair has also been investigated as a possible biomarker of manganese exposure. While some studies have found a correlation between exposure level and manganese concentration in hair (Collipp et al. 1983; Kondakis et al. 1989; Rosenstock et al. 1971), use of hair is also subject to a number of difficulties. For example, exogenous contamination may yield values that do not reflect absorbed doses, and hair growth and loss limits its usefulness to only a few months after exposure (Stauber et al. 1987). Thus, it is perhaps not surprising that other studies have found no correlation between individual hair levels and the severity of neurological effects in manganese -exposed persons (e.g., Stauber et al. 1987). 47 2. HEALTH EFFECTS 2.5.2 Biomarkers Used to Characterize Effects Caused by Manganese The principal adverse health effect associated with exposure to manganese is the neurological syndrome of manganism. The fully developed disease can be diagnosed by the characteristic pattern of symptoms and neurological signs (Mena et al. 1967; Rodier 1955), but the early signs and symptoms are not specific for manganese. However, careful neurological and psychomotor examination in conjunction with known exposure to manganese may be able to detect an increased incidence of preclinical signs of neurological effects in apparently healthy people (e.g., Iregren et al. 1990; Roels et al. 1987a). However, these signs are not sufficiently specific that preclinical effects of manganese may be reliably identified in an exposed individual. Measurement of altered levels of dopamine and other neurotransmitters in the basal ganglia has proved to be a useful means of evaluating central nervous system effects in animals (e.g., Bonilla and Prasad 1984; Eriksson et al. 1987a, 1987b), and these changes are often observed before any behavioral or motor effects are apparent (e.g., Bird et al. 1984). No noninvasive methods are currently available to determine if there are decreased dopamine levels in the brain of exposed humans, but decreased urinary excretion of dopamine and its metabolites has been noted in groups of manganese -exposed workers (Bernheimer et al. 1973; Siqueira and Moraes 1989). Reduced urinary excretion of 17-ketosteroids (perhaps as a consequence of decreased testosterone production) has been noted in many patients with neurological signs of manganism (Rodier 1955), but it is not known whether this change is detectable prior to the occurrence of neurological effects. 2.6 INTERACTIONS WITH OTHER CHEMICALS There is clear evidence from studies in animals that the gastro- intestinal absorption (and hence the toxicity) of manganese is inversely related to dietary iron concentrations. That is, high levels of iron lead to decreased manganese absorption and toxicity, and low levels of iron lead to increased manganese absorption and toxicity (Chandra and Tandon 1973; Diez- Ewald et al. 1968; Rehnberg et al. 1982). Conversely, high levels of dietary manganese lead to decreased iron absorption (Diez-Ewald et al. 1968; Thomson et al. 1971). Short-term effects of this sort are probably the result of kinetic competition between iron and manganese for a limited number of binding sites on intestinal transport enzymes (Thomson et al. 1971), while longer-term effects of iron deficiency or excess are probably due to adaptive changes in the level of intestinal transport capacity (Cotzias 1958). A similar inhibitory effect of cadmium on manganese uptake has been noted by Gruden and Matausic (1989). In addition, manganese appears to be capable of increasing the synthesis of the metal binding protein metallothionine (Waalkes and Klaassen 1985). Cadmium ion bound to metallothionine is less toxic than free cadmium, so manganese treatment can decrease the toxic effects of cadmium exposures (Goering and Klaassen 1985). 48 2. HEALTH EFFECTS Ethanol has been suspected as increasing the susceptibility of humans to manganese toxicity (e.g., Rodier 1955), but evidence to support this is limited. Singh et al. (1979) and Shukla et al. (1978) reported that concomitant exposure of rats to ethanol and manganese (as MnCl, in drinking water) led to higher levels of manganese in brain and liver than if manganese were given alone, and this was accompanied by increased effects as judged by various serum or tissue enzyme levels. Although the authors referred to these effects as "synergistic," the data suggest that the effects were more likely additive. There is some evidence from a study in animals that chronic administration of drugs such as chlorpromazine results in increased levels of manganese in the brain, including the caudate nucleus (Weiner et al. 1977). Chronic chlorpromazine treatment sometimes results in tardive dyskinesia, and manganese deposition in the brain might contribute to this. It is not known if excess manganese exposure increases the risk of chlorpromazine-induced dyskinesia. Intramuscular injection of animals with metallic nickel or nickel subsulfide (Ni,S,) normally leads to a high incidence of injection-site sarcomas, but this is reduced when the nickel is injected along with manganese dust (Sunderman et al. 1976). The mechanism of this effect is not clear, but natural killer cell activity normally undergoes a large decrease following nickel injection, and this is prevented by the manganese (Judde et al. 1987). The significance of this observation to humans exposed to nickel and/or manganese by the oral or inhalation routes is not clear. 2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE A number of researchers have observed that there is a wide range in the susceptibility of different individuals to the neurological effects of inhaled manganese dusts (Rodier 1955; Smyth et al. 1973; Tanaka and Lieban 1969). However, the reason for this variation is not certain. One likely factor is individual differences in the rates of manganese absorption and/or excretion, which can vary widely among different people (Saric et al. 1977). The basis of these toxicokinetic variations, in turn, may be due to differences in dietary levels of iron (Chandra and Tandon 1973; Mena et al. 1969; Thomson et al. 1971) or other metals (Chowdhury and Chandra 1987; Gruden and Matausic 1989), or to different levels of alcohol ingestion (Schafer et al. 1974; Shukla et al. 1978). Another factor which might be relevant is dietary protein intake, with low levels appearing to increase the effect of manganese on brain neurotransmitter levels in exposed animals (Ali et al. 1983a, 1983b, 1985). One group that has received special attention as a potentially susceptible population is the very young. This is mainly because a number of studies indicate that neonates retain a much higher percentage of ingested or injected manganese than adults, both in animals (Keen et al. 1986; Kostial et al. 1978; Rehnberg et al. 1980) and in humans (Zlotkin and Buchanan 1986). 49 2. HEALTH EFFECTS The basis for this high retention is not certain, but is presumably a consequence of increased absorption (Mena et al. 1974; Rehnberg et al. 1980) and/or decreased excretion (Kostial et al. 1978; Miller et al. 1975; Rehnberg et al. 1981), possibly because maternal milk is too low in manganese to provide for normal tissue levels (Ballatori et al. 1987). Regardless of the mechanism, the result of the high retention is an increase in the tissue levels of exposed neonatal animals (Miller et al. 1975; Rehnberg et al. 1980, 1981), especially in brain (Kontur and Fechter 1985, 1988; Kristensson et al. 1986; Kostial et al. 1978; Miller et al. 1975; Rehnberg et al. 1981). This has caused several researchers to express concern over possible toxic effects in human infants exposed to manganese in formula (Collipp et al. 1983; Keen et al. 1986; Zlotkin and Buchanan 1986). However, while there is some limited evidence that prenatal or neonatal exposure of animals to elevated levels of manganese can lead to neurological changes in the new-born (Deskin et al. 1980; Kristensson et al. 1986; Lown et al. 1984; Rehnberg et al. 1981), several researchers have not been able to obtain direct evidence that neonates are more susceptible to manganese-induced neurotoxicity than adults (Kontur and Fechter 1985, 1988; Kostial et al. 1978; Kristensson et al. 1986). Elderly people might also be somewhat more susceptible to manganese neurotoxicity than the general population. One factor that could contribute to this is a loss of neuronal cells, due either to aging (Silbergeld 1982) or to accumulated neurological damage from other environmental neurotoxins. Also, homeostatic mechanisms might become less effective in aged populations, leading to higher tissue levels following exposure. However, this has not been studied. Another group of potential concern is people with liver disease. This is because the main route of manganese excretion is via hepatobiliary transport (see Section 2.3.4), so individuals with impaired biliary secretion capacity would be expected to have diminished ability to handle manganese excesses. In support of this, Hambridge et al. (1989) reported that in a group of infants and children receiving parenteral nutrition, children with liver disease had higher average plasma concentrations of manganese than children without liver disease. With respect to the respiratory effects of inhaled manganese (bronchitis, pneumonitis), people with lung disease or who have exposure to other lung irritants may be especially susceptible. This is supported by the finding that inhalation of manganese dusts caused increased incidence of respiratory symptoms (wheezing, bronchitis) in smokers but not in nonsmokers among manganese alloy workers (Saric and Lucic-Palaic 1977). 2.8 MITIGATION OF EFFECTS This section will describe clinical practice and research concerning methods for reducing toxic effects of exposure to manganese. However, because some of the treatments discussed may be experimental and unproven, this section should not be used as a guide for treatment of exposures to manganese. 50 2. HEALTH EFFECTS When specific exposures have occurred, poison control centers and medical toxicologists should be consulted for medical advice. There is substantial evidence for interaction of iron and manganese in intestinal absorption (Chandra and Tandon 1973; Diez-Ewald et al. 1968; Keen and Zidenberg-Cher 1990; Mena et al. 1969; Rehnberg et al. 1982). Cawte et al. (1989) cite low levels of iron and calcuim as "synergistic factors" that impact on the toxic effects associated with manganese exposures. Anemic persons were also considered more susceptible to the toxic effects of manganese due to their enhanced absorption of iron and manganese through similar uptake mechanisms (Cotzias et al. 1968). Evidence from these reports suggest that it may be possible to prevent or reduce the severity of future toxic effects caused by current and future exposure to manganese through specific dietary supplementation. For example, ensuring sufficient iron or calcium stores, as opposed to a deficiency in these or other minerals, may alter manganese absorption, potentially reducing toxicity by reducing uptake. It is not known whether ensuring iron and calcium sufficiency will reduce toxic effects of manganese once it has been absorbed into the body, because information on critical levels of manganese at target sites is not known. Orally absorbed manganese is taken up by the liver through a passive, mediated transport mechanism (Keen and Zidenberg-Cher 1990). Inhaled manganese is readily absorbed by the lungs, although some may be retained there. Larger particles of dust containing manganese may be transported by mucociliary transport from the throat to the gut (Drown et al. 1986). Once in the plasma, manganese is reportedly transported by transferrin in the plasma, however, information on the mechanism of uptake in extrahepatic tissues is limited (Keen and Zidenberg-Cher 1990). Chelation therapy with agents such as edetic acid may alleviate some of the neurological signs of manganism, but not all patients show improvement, and some of the improvement may not be permanent (Cook et al. 1974). A study in monkeys reported a long half-life of manganese in the brain following inhalation exposure (Newland et al. 1987). Given that neurotoxicity is of concern with manganese exposure, knowledge of the mechanisms behind this longer half-life in the brain may be central to the development of mitigation methods. Newland et al. reported that this long half-life reflected both redistribution of manganese from other body depots, and a slow rate of clearance from the brain. A later study reported that elevated levels in the brain persisted after inhalation exposure (due to redistribution), whereas for subcutaneous exposure, levels declined when administration was stopped (Newland et al. 1989). These authors also reported that the accumulation of manganese in the brain was preferential in specific regions, but was unrelated to the route of exposure (Newland et al. 1989). In addition, the authors stated that there are no known mechanisms or "complexing agents" that have been shown to remove manganese from the brain. 51 2. HEALTH EFFECTS The neurological injury produced by prolonged excess manganese exposure is mainly irreversible, and treatment for manganese intoxication is mainly supportive (Ellenhorn and Barceloux 1988). Antiparkinsonian drugs, such as L-dopa, have been shown to reverse some of the neuromuscular signs of manganism (Rosenstock et al. 1971), but these drugs can produce a variety of side effects and are not always effective (Cook et al. 1984; Ellenhorn and Barceloux 1988; Haddad and Winchester 1990). The valence state of manganese may influence both its retention in the body (see Section 2.3.3) and its toxicity (see Section 2.4). Therefore, it is possible that interference with oxidation of manganese could be a method for preventing manganese cellular uptake and toxicity. Regarding retention, one study suggests that clearance is much more rapid for divalent manganese (Mn'?) than for trivalent manganese (Mn*?®) (Gibbons et al. 1976). Regarding neurotoxicity, trivalent manganese appears to be more efficient in enhancing the oxidation of catechols than either di- or tetravalent manganese (Mn'*) (Archibald and Tyree 1986). Thus, it is plausible that preventing the formation of trivalent manganese could possibly both enhance elimination and prevent neurotoxicity. Ceruloplasmin is involved in the oxidation of iron and has also been involved in the oxidation of divalent manganese ion to the trivalent state (Gibbons et al. 1976). Selective inhibition of this oxidative function may be a method of mitigating the toxic effects of exposure of manganese. However, inhibition of the oxidation of manganese might also result in adverse effects on transport and cellular uptake of other essential metals as well, especially iron. Furthermore, it is not completely clear how the valence state of manganese is related to its normal function in neural cells and how this role is altered in manganese toxicity. Both Mn'?> and Mn*’ have been reported as components of metaloenzymes (Keen and Zidenberg-Cher 1990; Leach and Lilburn 1978; Utter 1976). Manganese was shown to catalyze the oxidation of dopamine in vitro. These studies reported that the toxicity induced by manganese resulted from the depletion of dopamine and the production of dopamine quinone and hydrogen peroxide through this mechanism. Antioxidants were tested for their ability to inhibit the dopamine oxidation induced by manganese and it was found that ascorbic acid and thiamine completely inhibited dopamine oxidation both in the presence and absence of manganese (Cawte et al. 1989). The report did not include data on background oxidation levels nor on the extent of dopamine oxidation in the absence of manganese. Results from the antioxidant treatment were viewed as evidence for their use in mitigating the adverse effects of manganese. Because dopamine oxidation was inhibited to some degree in the absence of manganese, these data could alternately be interpreted to suggest a more complex mechanism than the direct action of manganese to induce dopamine oxidation and subsequent cell toxicity. Further investigation of the inhibition of manganese oxidation as a possible mitigation method should be preceded by additional studies to elucidate the role of manganese in its various valence states in normal neuronal cell metabolism. 52 2. HEALTH EFFECTS 2.9 ADEQUACY OF THE DATABASE Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate information on the health effects of manganese is avajlable. Where adequate information is not available, ATSDR, in conjunction with the National Toxicology Program (NTP), is required to assure the initiation of a program of research designed to determine the health effects (and techniques for developing methods to determine such health effects) of manganese. The following categories of possible data needs have been identified by a joint team of scientists from ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that, if met, would reduce or eliminate the uncertainties of human health assessment. In the future, the identified data needs will be evaluated and prioritized, and a substance-specific research agenda will be proposed. 2.9.1 Existing Information on Health Effects of Manganese The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to manganese are summarized in Figure 2-3. The purpose of this figure is to illustrate the existing information concerning the health effects of manganese. Each dot in the figure indicates that one or more studies provide information associated with that particular effect. The dot does not imply anything about the quality of the study or studies. Gaps in this figure should not be interpreted as "data needs" information (i.e., data gaps that must necessarily be filled). As the upper part of the figure reveals, studies in humans have focused mainly on intermediate and chronic inhalation exposure, and the resulting neurological effects. There are a few reports of humans exposed by the oral route, and these too have focused on neurological effects. Reproductive effects have been studied in men exposed to manganese by inhalation, but other effects have generally not been formally investigated. Manganese toxicity has been investigated in numerous animal studies, both by the oral and the inhalation routes. These studies have included most endpoints of potential concern, although in vivo studies of immunotoxicity are lacking. The dermal route does not appear to be of significant concern, and has not been investigated. 2.9.2 Data Needs Presented below is a brief review of available information, and a discussion of research needs. Dermal studies are not discussed, since there is no evidence that dermal to manganese exposure is of health concern. 53 2. HEALTH EFFECTS FIGURE 2-3. Existing Information on Health Effects of Manganese SYSTEMIC / Se & oo & & Ka © <> o & & & ° oR & xf & & § Qo L & 5 <2 & nd & Q ¥ & & FF Q® QF ® ® Inhalation | 0 é © Oral & oO Dermal HUMAN SYSTEMIC / S/o © & & & & & se SESS S/S SESE SUYSEL SF Inhalation o|0|0O e|0|0O Oral o oO | 0/00 0 Dermal ANIMAL @ Existing Studies 54 2. HEALTH EFFECTS Acute-Duration Exposure. Studies in animals and humans indicate that inorganic manganese compounds have very low acute toxicity by any route of exposure. An exception is KMnO,, which is a powerful oxidant that can cause severe corrosion of skin or mucosa at the point of contact (Southwood et al. 1987). Acute inhalation exposure to high levels of manganese dusts (MnO,, Mn,0,) can cause an inflammatory response in the lung, which can lead to impaired lung function (Maigetter et al. 1976; Shiotsuka 1984). However, this response is characteristic of nearly all inhalable particulate matter (EPA 1985d), and is not dependent upon the manganese content of the particle. Large oral doses of highly concentrated solutions of manganese salts given by gavage can cause death in animals (Holbrook et al. 1975; Kostial et al. 1978; Smith et al. 1969), but oral exposures via food or water have not been found to cause significant acute toxicity (Gianutsos and Murray 1982; Hejtmancik et al. 1987a, 1987b). In order to derive acute MRL values, further studies would be helpful to define the threshold for adverse effects following acute exposure to manganese in soil, water, or air. However, it does not seem that exposure levels likely to be encountered around waste sites would be high enough to be of acute concern. Intermediate-Duration Exposure. Intermediate-duration exposure of humans to manganese compounds can lead to central nervous system effects (Rodier 1955). However, reliable estimates of intermediate-duration NOAELs or LOAELs for neurotoxicity in humans are not available. Intermediate-duration inhalation studies in animals have yielded NOAEL and LOAEL values for biochemical and neurobehavioral effects (Coulston and Griffin 1977; Lown et al. 1984; Morgante et al. 1985; Ulrich et al. 1979a, 1979b), but these are too far apart (two orders of magnitude) to define a threshold. Moreover, most animals (especially rodent species) do not develop the ataxia, tremor, or bradykinesia characteristic of manganese toxicity in humans. For these reasons, it is concluded that these data are not sufficient to derive an intermediate-duration inhalation MRL. Further epidemiological studies in occupationally exposed human populations to define the intermediate-duration exposure levels that are associated with neurological effects would be valuable. Intermediate-duration oral exposure of humans to manganese has been reported to cause neurotoxicity in two cases (Holzgraefe et al. 1986; Kawamura et al. 1941), but the data are too limited to judge if these effects were due entirely to the manganese exposure, or to define the threshold. Further epidemiological or case reports of humans ingesting high levels of manganese would be valuable in evaluating the health risk of intermediate-duration oral exposure, and to obtain sufficient dose-response data to derive an MRL. Additional oral studies in animals may be valuable in revealing cellular and molecular mechanisms of manganese neurotoxicity, but would probably not be helpful in estimating the human MRL due to the apparent difference in dose sensitivity between humans and animals. Chronic-Duration Exposure and Cancer. Studies in humans make clear that the main health effect following chronic inhalation exposure is nervous system toxicity (Emera et al. 1971; Mena et al. 1967; Rodier 1955; Schuler et al. 55 2. HEALTH EFFECTS 1957; Smyth et al. 1973). Available data (Iregren 1990; Roels et al. 1987a) are sufficient to derive a chronic inhalation MRL, although additional human studies would be valuable to identify the threshold for neurological effects with greater certainty. Chronic inhalation studies in nonhuman primates (Bird et al. 1984; Coulston and Griffin 1977) indicate that animals are not as sensitive to the neurological effects of manganese as humans. Because of this apparent difference in susceptibility, additional studies in animals could be valuable in increasing our understanding of the mechanism of this disease and the basis for the difference between humans and animals, but probably would not be as helpful as additional human studies in improving the inhalation MRL. Some data on neurological or other health effects in humans from chronic oral intake of manganese exist (Cawte et al. 1987; Kondakis et al. 1989), but these studies are limited by uncertainties in exposure route, total exposure level, and the influence of confounding factors. Similarly, there are a few (mainly negative) chronic oral exposure studies in animals (Gupta et al. 1980; Hejtmancik et al. 1987a, 1987b; Lai et al. 1984; Nachtman et al. 1986), but these studies do not provide sufficient information to determine dose levels or effects of concern following chronic oral exposure. Based on this absence of data in both humans and animals, no chronic oral MRL has been derived. Additional chronic oral studies, especially epidemiological studies, would be valuable in determining the safe ingestion level of manganese by humans. Chronic inhalation exposure of humans to manganese dusts has not been reported to be associated with increased risk of cancer, but no formal studies were located to provide direct data on this point. Epidemiological investigations of the cause of death in manganese miners or other occupationally-exposed groups would be valuable to strengthen the database on this subject. Chronic oral exposure of rats and mice to high doses of manganese sulfate has provided marginal evidence of carcinogenic potential. However, the effects were small and were not consistent across sexes or species, suggesting that the carcinogenic potential, if any, is small. Further studies in animals would be valuable to clarify the significance of these rather equivocal data. Genotoxicity. No studies were located regarding genotoxic effects of manganese in humans. Studies in intact organisms (fruit flies and rats) have been negative (Dikshith and Chandra 1978; Rasmuson 1985; Valencia et al. 1986), but in vitro studies in bacteria, yeast, and cultured mammalian cells have yielded mixed, but mainly positive, results (Casto et al. 1979; Kanematsu et al. 1980; Nishioka 1975; Oberley et al. 1982; Orgel and Orgel 1965; Singh 1984; Ulitzur and Barak 1988; Wong 1988; Zakour and Glickman 1984). Additional studies, especially in cultured mammalian cells or in lymphocytes from exposed humans, would be valuable in clarifying the genotoxic potential of manganese. Reproductive Toxicity. Men who are exposed to manganese dust in workplace air often develop impotency (Emara et al. 1971; Mena et al. 1967; Rodier 1955), and studies in animals indicate that manganese can cause direct damage to the testes (Chandra et al. 1973; Seth et al. 1973). Additional studies in occupationally-exposed men would be valuable to provide reliable 56 2. HEALTH EFFECTS exposure-response data on reproductive function (impotence, libido, number of children), and to determine if the testes are damaged directly from exposure to manganese. Information on adverse reproductive effects in women is not available, and data from studies in female animals are sparse. Epidemiological studies on the effects of manganese on reproductive function in women exposed in the workplace, and single-generation reproductive studies of female animals exposed by the oral or inhalation routes, would both be valuable in establishing whether or not this is a human health concern. Developmental Toxicity. One study (Kilburn 1987) has investigated the incidence of birth defects in a human population exposed to high levels of manganese in the environment, but the results are not clear. For this reason, additional studies on this population or other groups exposed to high levels of manganese would be valuable to determine if an above-average incidence of birth defects occurs, and if so, to determine the exposure route and manganese exposure level of concern. A few studies in animals have provided evidence for developmental effects when exposure occurs by inhalation (Lown et al. 1984) or by intraperitoneal injection (Webster and Valois 1987), but dose- response relationships have not been established. Further studies in animals that focus on identifying the threshold for developmental effects following oral and inhalation exposure would be valuable in judging the risk of developmental effects in humans exposed to manganese near hazardous waste sites or in the workplace. Immunotoxicity. Studies in animals indicate that injection of manganese compounds can cause significant changes in the functioning of several cell- types of the immune system (Rogers et al. 1983; Smialowicz et al. 1985, 1987). However, it is not known if these changes are associated with significant impairment of immune system function. Further studies would be valuable to determine whether these effects also occur after oral and/or inhalation exposure in animals or humans. If so, a battery of immune function tests would then be valuable in determining if these changes result in a significant impairment of immune system function. Neurotoxicity. Studies of humans exposed to high levels of manganese dust in the workplace provide clear evidence that the chief health effects of concern following manganese exposure is injury to the central nervous system (Emera et al. 1971; Mena et al. 1967; Rodier 1955; Schuler et al. 1957; Smyth et al. 1973). Quantitative data on exposure levels for chronic durations are sufficient to identify a LOAEL for neurological effects (Iregren 1990; Roels et al. 1987a), but additional epidemiological studies of workers exposed to low levels (below 1 mg/m?) would be valuable to confirm and refine the safe limits of inhalation exposure. In addition, studies of possible neurological effects in persons living near factories or waste sites where manganese is found would be helpful in judging if exposures from such sources are of public health concern. Neurotoxicity in humans has not been clearly associated with oral exposure to manganese, although there are several studies (Holzgraefe et al. 1986; Kawamura et al. 1941; Kilburn 1987; Kondakis et al. 1989) that provide 57 2. HEALTH EFFECTS suggestive evidence that this may occur. Studies in rodents and nonhuman primates indicate that oral intake of high doses of manganese can lead to biochemical and behavioral changes indicative of nervous system effects (Bonilla and Prasad 1986; Chandra 1983; Gupta et al. 1980; Kristensson et al. 1986; Lai et al. 1984; Nachtaan et al. 1986), and this is supported by intravenous studies in monkeys (Newland and Weiss 1992). However, neither rodents nor monkeys appear to be as susceptible to manganese neurotoxicity as humans. Further studies in animals to determine the basis for the apparent differences in route and species susceptibility could be helpful in understanding the mechanism of manganese neurotoxicity, and in choosing an animal species most appropriate to serve as a model for humans. Also of value would be additional studies on the cellular and biochemical basis of manganese neurotoxicity, including a more detailed analysis of precisely which neuronal cell types are damaged, and why. This could be helpful in developing therapies for treating individuals with manganese-induced disease, and could also be helpful in understanding and treating individuals with similar neurological lesions (e.g., Parkinson's disease). Epidemiological and Human Dosimetry Studies. As already noted, there are numerous epidemiological studies of workers exposed to manganese dusts in air, and the clinical signs and symptoms of the resulting disease are well- established. However, these studies have only involved males, and have only involved the inhalation route of exposure. Additional epidemiological studies that focus on females who are exposed to manganese dust in the workplace, and on populations exposed to above average oral intakes (either through water or food), would be valuable in strengthening conclusions on no-effect exposure levels. This would be helpful in evaluating risks to people who may be exposed to above-average manganese levels near waste sites. Biomarkers of Exposure and Effect. Studies in humans have shown that it is difficult to estimate past exposure to manganese by analysis of manganese levels in blood, urine, feces, or tissues (Roels et al. 1987b; Smyth et al. 1973; Valentine and Schiele 1983; Yamada et al. 1986). This is the result of several factors: (1) manganese is a normal component of the diet and is present in all human tissues and fluids, so above-average exposure must be detected as an increase over a variable baseline; (2) manganese is rapidly cleared from blood, and is excreted mainly in the feces, with very little in the urine; and (3) manganese absorption and excretion rates are subject to homeostatic regulation, so above-average exposures may result in only small changes in fluid or tissue levels. Probably the most relevant indicator of current exposure is tissue levels of manganese, but at present this can only be measured in autopsy or biopsy samples. Studies on noninvasive methods capable of measuring manganese levels in vivo, either in the whole body or in specific organs (e.g., brain), would be very helpful in identifying persons with above-average exposure. The principal biological markers of manganese effects are changes in the levels of various neurotransmitters and related enzymes and receptors in the 58 2. HEALTH EFFECTS basal ganglia (Bonilla and Prasad 1984; Bird et al. 1984; Eriksson et al. 1987a, 1987b). Development of noninvasive methods to detect preclinical changes in these biomarkers or in the functioning of the basal ganglia would be valuable in identifying individuals in whom neurological effects might develop. Further efforts to determine the correlation between urinary excretion levels of neurotransmitters, neurotransmitter metabolites, and/or 17-ketosteroids (Bernheimer et al. 1973; Rodier 1955; Siqueira and Moraes 1989) and the probability or severity of neurological injury in exposed people would also be valuable. Absorption, Distribution, Metabolism, and Excretion. The toxicokinetics of manganese absorption, distribution, and excretion have been studied in both humans and animals. Oral absorption is about 3%-5% in humans (Davidsson et al. 1988, 1989; Mena et al. 1969), but the rate may vary depending on age and dietary iron and manganese intake levels (Chandra and Tandon 1973; Diez- Ewald et al. 1968; Rehnberg et al. 1982; Thomson et al. 1971). Absorption may also depend upon the chemical form of manganese ingested, but data on this are lacking. By the inhalation route, the rate and extent of manganese uptake in the lung (as opposed to uptake of manganese in the gut following mucociliary transport of particles from the lung to the stomach) has not been measured. As part of the investigation, data on differences in uptake as a function of chemical species (MnO,, Mn,0,) and particle type and size would also be valuable in assessing human health risk from different types of manganese dusts. Manganese appears to be distributed to all tissues, including brain (Kristensson et al. 1986; Rehnberg et al. 1980, 1981, 1982). Further studies would be valuable on the rate and extent of manganese uptake into the brain, since this is probably a critical step in manganese neurotoxicity. In addition, the metabolism of manganese (specifically, the degree and the rate of valence state interconversions) has not been thoroughly investigated. Data on this topic would be valuable in understanding the mechanism of manganese toxicity, and would help in evaluating the relative toxicity of different manganese compounds. Excretion of manganese is primarily through the feces (Drown et al. 1986; Klaassen 1974; Mena et al. 1969). Because the rate of excretion is an important determinant of manganese levels in the body, further studies would be valuable on the biochemical and physiological mechanisms which regulate manganese excretion. Comparative Toxicokinetics. Exposure of animals to manganese by either the oral or inhalation routes does not usually result in appearance of the neurological symptoms characteristic of manganism in humans (Bird et al. 1984; Bonilla and Prasad 1984; Chandra 1983; Coulston and Griffin 1977; Gray and Laskey 1980; Lai et al. 1984; Nachtman et al. 1986; Ulrich et al. 1979a, 1979b). The reason for this apparent difference between humans and animals is not clear, but could be due, at least in part, to toxicokinetic differences between manganese absorption, distribution, metabolism, and excretion in humans and animals. For this reason, thorough comparative studies of manganese toxicokinetics in humans and animals would be valuable in identifying which species is the most appropriate model for studying health effects in humans. 59 2. HEALTH EFFECTS Mitigation of Effects. Recommended methods for the mitigation of manganese toxicity (manganism) are mainly supportive (Ellenhorn and Barceloux 1988). Administration of antiparkinsonian drugs and chelation therapy are sometimes effective in reducing some of the symptoms, (Ellenhorn and Barceloux 1988; Haddad and Winchester 1990), but are not effective in all cases. In this regard, studies on the efficacy of newly developed anti-Parkinson drugs and newly developed chelators would be valuable. No information was located concerning mitigation of effects of low-level, long-term exposure to manganese. Further information on the safety and efficacy of possible methods for treating manganese-exposed populations in the vicinity of hazardous waste sites would be valuable. 2.9.3 On-going Studies A number of research projects are in progress investigating the health effects and the toxicokinetics of manganese. Projects sponsored by the federal government are summarized in Table 2-7. 2. 60 HEALTH EFFECTS TABLE 2-7. On-going Studies on Manganese Research Investigator Affiliation description Sponsor K. Anger NIOSH, Neurotoxicity from exposure to NIOSH Cincinnati, OH heavy metals. D. H. Baker Animal Science, Effect of dietary components USDA Urbana, IL on bioavailability of nutrients and drugs. K. L. Beattie Baylor College Biochemical study of error- USDHHS of Medicine, prone DNA synthesis in Houston, TX bacteria. G. L. Czarnecki Animal Science, Effects of arsenic on trace USDA Urbana, IL mineral utilization. G. Eichhorn National Effects of metals and proteins USDHHS Institutes of on nucleic acids. Health, Bethesda, MD G. Gianutsos University of Evaluation of effects of USDHHS Connecticut, manganese on central nervous Storr, CT system in mice and rats. L. S. Hurley University of Genetic/nutritional USDA California, interactions in development. Davis, CA L. S. Hurley University of Nutritional factors in USDA California, mammalian development. Davis, CA B. L. Lonnerdal University of Absorption of manganese in USDA California, Davis, CA humans. 2. 61 HEALTH EFFECTS TABLE 2-7 (Continued) Research Investigator Affiliation description Sponsor F. H. Nielsen Agricultural Ultratrace elements (arsenic, USDA Research boron, nickel, vanadium, etc.) Service, in nutrition. Grand Forks, ND G. Oberdoerster University of Pulmonary toxicity of metals USDHHS Rochester, in rats and primates. Rochester, NY Q. Oberdoerster University of Effects of complexing agents USDHHS Rochester, on pulmonary clearance of Rochester, NY metals in rats. Q. Oberdoerster University of Effect of inhalation of USDHHS Rochester, cadmium and manganese Rochester, NY compounds on lung cells in mammals. A. C. Peters Columbus, OH Chronic oral toxicity of USDHHS manganese sulfate monodydrate and triameterene on rats and mice. T. G. Rossman New York Mutagenicity of USDHHS University, environmentally significant New York, NY metals. D. B. Thomas Fred Hutchinson Cancers of the larynx, USDHHS Cancer Research Center, Seattle, WA esophagus, and mouth from trace elements in humans. 2. 62 HEALTH EFFECTS TABLE 2-7 (Continued) Research Investigator Affiliation description Sponsor B. Weiss University of Neurobehavioral toxicity of USDHHS Rochester, organic lead and manganese in Rochester, NY primates. B. Weiss University of Model of manganese toxicity in USDHHS Rochester, primates (monkeys) . Rochester, NY B. Weiss University of Neurobehavioral toxicity of Not Rochester, organometallic fuel additives. reported Rochester, NY B. Weiss University of Neurotoxicity of manganese in USDHHS Rochester, primates. Rochester, NY DNA = deoxyribonucleic acid; NIOSH = National Institute for Occupational Safety and Health; USDA = U.S. Department of Agriculture; USDHHS = U.S. Department of Health and Human Services 63 3. CHEMICAL AND PHYSICAL INFORMATION 3.1 CHEMICAL IDENTITY Table 3-1 lists common synonyms, trade names, and other pertinent identification information for manganese and several of its most important compounds. 3.2 PHYSICAL AND CHEMICAL PROPERTIES Table 3-2 lists important physical and chemical properties of manganese and several of its most important compounds. TABLE 3-1. Chemical Identity of Manganese and Compounds? Manganous Manganous Manganese Manganese Potassium Characteristic Manganese chloride sulfate tetroxide dioxide permangante Synonyms Elemental Manganese Manganese Trimanganese Manganese Permanganic manganese ; chloride”; sulfate tetroxide; peroxide; acid, potassium collodial manganese mangano- manganese salt®; chameleon manganese ; dichloride manganic oxide® binoxide; mineral® cutaval manganese black; battery manganese Trade name No data No data No data No data No data No data Chemical formula Mn MnCl, MnsSO, Mn,0, MnO, KMnO,, 0 oO Chemical structured cr = 2 ° a s I _ Mn Mn+2 Mn+2 s7 No data ry K' O—Mn=0 c oN oi. © I Oo oO 0 Coordination number 6 4 4 No data 6 4 0 Geometry Octahedral Tetrahedral Planar Distorted Octahedral Tetrahedral spinet Identification numbers: CAS Registry 7439-96-5 7773-01-5 7785-87-17 1317-35-27 1313-13-9 7722-64-7 NIOSH RTECS 009275000" 009625000" 0P1050000P No data No data SD6475000P EPA Hazardous Waste No data No data No data No data No data No data OHM/TADS No data No data No data No data No data 7217279 DOT/UN/NA/ No data No data No data No data No data UN1490P IMCO Shipping co 5.1° HSDB 00550 02154P 02187° No data No data 01218° NCI No data No data No data No data No data No data 3a11 information obtained from Sax and Lewis 1987, except where noted. busps 1989 SWindholz 1983 Cotton and Wilkinson 1962 CAS = Chemical Abstracts Service: Dangerous Goods Code: EPA Environmental Protection Agency: HSDB = Hazardous Substances Data Bank; NCI 0il and Hazardous Materials/Technical Assistance Data NIOSH = National Institute for Occupational Safety and Health: OHM/TADS System: RTECS = Registry of Toxic Effects of Chemical Substances DOT/UN/NA/IMCO = Department of Transportation/United Nat ions/North Ameri ca/lnternational Maritime = National Cancer Institute; t NOILVWIOANI TVDISAHd ANV TVOIWHHO 79 TABLE 3-2. Physical and Chemical Properties of Manganese and Compounds® Manganous Manganous Property Manganese chloride sulfate Formula Mn MnCl, MnSO, Valence 0 +2° +2 Molecular weight 54. 94° 125.84¢ 151.00° Color Silver Reddish Pale rose-red Physical state Solid Solid Solid Melting point 1,244°C? 650°C 700°C Boiling point 1,962°c? 1,190°c? Decomposes at 850°C Density at 20°C 7.20¢ 2.97 3.25% Odor No data No data Odorless Odor threshold: Water No data No data No data Air No data No data No data Solubility: Water Decomposes 723 g/L (25°C)? 520 g/L (5°C)¢ 700 g/L (70°C)? Acids Dissolves in No data No data Organic solvents Partition coefficients: Log octanol/water Log Ko, Vapor Pressure Henry’s law constant Autoignition temperature Flashpoint Flammability limits Conversion factors Explosive limits dilute mineral acids‘ No data No data No data 1 mmHg at 1,292°C® No data No data No data No data Not applicable No data Soluble in alcohol, insoluble in ether No data No data 10 mmHg at 778°C’ No data Noncombustible No data No data Not applicable No data Insoluble in alcohol No data No data No data No data No data No data No data Not applicable No data € NOILVIWJOANI TVOISAHd ANV TVDOIWIHD S9 TABLE 3-2 (Continued) Manganese Manganese Potassium Property tetroxide dioxide permanganate Formula Mn,0, MnO, KMnO, Valence +2, +3 +4° +7 Molecular weight 228.79 86.94° 158.03° Color Brownish Black Purple Physical state Solid Solid Solid Melting point 1,564°C Loses oxygen at 553°C? Decomposes at 240°C Boiling point No data No data No data Density at 20°C 4.856° 5.026" 2.703 Odor No data No data Odorless Odor threshold: Water No data No data No data Air No data No data No data Solubility: Water Insoluble Insoluble 63.8 g/L (20°C)? Acids Soluble in Soluble in Soluble in hydrochloric acid hydrochloric acid sulfuric acid? Organic solvents No data No data Soluble in acetone Partition coefficients: Log octanol/water No data No data No data Log Ki No data No data No data Vapor Pressure No data No data No data Henry’s law constant No data No data No data Autoignition temperature No data No data No data Flashpoint No data No data No data Flammability limits No data No data No data Conversion factors Not applicable Not applicable Not applicable Explosive limits No data No data No data aAll information obtained from Sax and Lewis 1987, except where noted. "EPA 1984b “‘Windholz 1983 Weast 1985 t NOILVWIOJINI TVOISAHd ANV TVOIWIHO 99 67 4. PRODUCTION, IMPORT, USE, AND DISPOSAL 4.1 PRODUCTION Manganese is an abundant element comprising about 0.1% of the earth's crust (Graedel 1978). It does not occur naturally as the base metal, but is a component of over 100 minerals, including various sulfides, oxides, carbonates, silicates, phosphates and borates (NAS 1973). The most commonly occurring manganese-bearing minerals include pyrolusite (manganese dioxide), rhodochrosite (manganese carbonate) and rhodanate (manganese silicate) (EPA 1984a; HSDB 1989; NAS 1973; Windholz 1983). Most manganese ore is used to produce ferromanganese (a manganese-iron alloy widely used in the production of steel) by smelting in electric furnaces (EPA 1984a; NAS 1973). Approximately 2 tons of manganese ore are required to make 1 ton of ferromanganese (NAS 1973). Production of 97%-98% pure manganese metal is achieved by aluminum reduction of low iron-content manganese ore (HSDB 1989), or from the byproducts of ferromanganese production. Manganese in higher purity is produced electrolytically from manganese sulfate solution (EPA 1984a; HSDB 1989). Manganese compounds are produced either from manganese ores or from manganese metal. For example, manganese chloride is produced by the reaction of hydrochloric acid with manganese oxide or manganese carbonate (HSDB 1989), manganese sulfate is produced by the action of sulfuric acid on manganese compounds (HSDB 1989), and potassium permanganate is produced by the electrolytic oxidation of manganese dioxide in potassium hydroxide solution (HSDB 1989; Sax and Lewis 1987). The organomanganese compound methylcyclo- pentadienyl manganese tricarbonyl (MMT) is produced by the reaction of manganous chloride, cyclopentadiene and carbon monoxide in the presence of manganese carbonyl (EPA 1984a; HSDB 1989; Sax and Lewis 1987). Most manganese is mined in open-pit or shallow underground mines (EPA 1984a; HSDB 1989; NAS 1973). Manganese ores were previously mined in the United States, but no appreciable quantity has been mined in the United States since 1978 (U.S. Bureau of Mines 1989). Rather, essentially all manganese ore used in manganese production in the United States is imported. Currently there are 65 facilities in the United States which indicate that they produce manganese or its compounds (TRI 1989). These 65 facilities are scattered across the United States, with the largest numbers in Pennsylvania (13) and Ohio (8). Over 870 facilities are involved in the distribution or use of manganese or manganese compounds (TRI 1989). Table 4-1 lists the number of facilities in each state, the ranges of the amounts stored at each facility, and the uses of the material (TRI 1989). The TRI data should be used with caution since the 1987 data represent first-time reporting by these facilities. This is not an exhaustive list. 68 4, PRODUCTION, IMPORT, USE, AND DISPOSAL TABLE 4-1. Facilities That Manufacture or Process Manganese and Compounds* Range of maximum No. of amounts on site facil- in thousands State” ities of pounds‘ Activities and uses‘ AK 1 1-9 4, 9 AL 36 (3)° 1-499,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 AR 9 10-9,999 4, 7, 8, 9, 13 AZ 2 1-9 B, 9 CA 27 0-999 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 12, 13 co 10 1-499,999 2, 3,5,7, 8,9, 1, 13 CT 13 0.1-9,999 2, 3,8,9 10, 11, 12, i3 DE 2 10-999 5, 11 FL 18 (1)° 0.1-999 3, 5,7, 8, 9, 10, 13 GA 18 (3)° 1-999 5, 7, 8, 9, 10, 12, 13 IA 35 (2)° 1-999 2, 3,4, 5,8, 9, 10, 11, 13 ID 2 100-9,999 1; 5, 13, 12 IL 52 (2)° 0.1-49,999 1; 2,3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13 IN 44 (3)° 1-49,999 2, 3, 4,7, 8, 9, 10, 12, 13 KS 9 1-499,999 1, 3, 4, 6, 7, 8, 9, 12 KY 23 (1)° 0.1-49,999 1, 2, 4, 5,7, 8, 9, 12 LA 4 1-9,999 8, 9, 13 MA 7 {1)* 1-999 3, 5,8, 9, 10, 13 MD 15 1-99,999 1, 2, 3,4, 5,6,7,8,9, 10, 11, 12 ME 3 0.1-99 2; 3, 9; 13 MI 43 (2)° 0.1-49,999 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13 MN 9 (1)° 0.1-98% 3, 4, 6, 8, 9, 10, 13 MO 20 (2)° 1-49,999 2, 3,5,7,8, 9,10, 11, 12, 13 MS 11 (2)° 1-49,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 MT 1 10-99 8 NC 20 1-9,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 ND i 10-99 9 NE 10 (1)* 1-9,999 1, 2, 3, 4, 5, 8, 9 NH 2 (1)° 0-0.09 9, 13 NJ 28 (1)° 0-9,999 1, 2, 8, 4, 5, 6,7, 8, 9, 10, 11 NM 2 1-99 8, 9 NV 2 10-9,999 1, 2, 4, 7 NY 31 @1)° 1-9,999 1, 2, 3, 4, 5,7, 8, 9, 10, 11, 12 OH 105 (6)° 0-499,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 OK 13 1) 0.1-499,999 2, 5,86, 7, 8, 9, 12, 13 OR 12 1-999 1, 5, 7, 8, 9, 12, 13 PA 97 (3)° 0-99,999 1, 2, 3, 4, 5,6, 7,8, 9, 10, 12, 12 PR 2 1-9 8, 13 RI 2 10-99 9 SC 25 (2)° 0-49,999 1, 2, 3, 4,5, 6,7, 8, 9, 10, 11, 12, 13 SD 1 0-0.09 8, 12 TN 27 0-49,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 TX 48 (3)° 0.1-49,999 1, 2, 4%, 5, 6, 7, 8, 9, 10, 11, 12, 13 uT 4 10-49,999 8, 9 VA 18 (1)° 1-9,999 3, 5, 8,9, 12, 13 vT 1 0-0.09 12, 13 WA 23 (1)° 1-999 1, 2, 3, 4, 5, 7, 8, 9, 10, 12 WI 47 (1)° 0.1-499,999 1, 3, 5,8, 9, 10, 11, 12, 13 wv 12 (1)° 10-49,999 1, 2, 3, 4, 5,7, 8, 9, 10, 11, 12 TRI 1989 Post office state abbreviations Data in TRI are maximum amounts on site at each facility. dActivities/Uses: 1. produce 8. as a formulation component 2. import 9. as an article component 3. for on-site use/processing 10. for repackaging only 4. for sale/distribution 11. as a chemical processing aid 5. as a byproduct 12. as a manufacturing aid 6. as an impurity 13. ancillary or other use 7. as a reactant Number of facilities reporting "no data" regarding maximum amount of the substance on site. 69 4. PRODUCTION, IMPORT, USE, AND DISPOSAL 4.2 IMPORT/EXPORT The United States currently relies on imports to fill its need for manganese. Imports of manganese ore have increased from 680 million pounds in 1984 to 1,100 million pounds in 1988, and were expected to reach 1,500 million pounds in 1989 (HSDB 1989; U.S. Bureau of Mines 1989). No information was located regarding predicted future trends. Ferromanganese is also imported, with import quantities ranging from 730 to 990 million pounds per year (HSDB 1989). Ferromanganese exports are very small, ranging from 0.007 to 0.013 million pounds per year during the period 1984-1988 (HSDB 1989; U.S. Bureau of Mines 1989). 4.3 USE Metallic manganese (ferromanganese) is used principally in steel production to improve hardness, stiffness and strength. It is used in carbon steel, stainless-steel, high-temperature steel, and tool-steel, along with cast iron and superalloys (EPA 1984a; HSDB 1989; NAS 1973). Manganese compounds have a variety of uses. Manganese dioxide is commonly used in production of dry-cell batteries, matches, fireworks, porcelain and glass- bonding materials, amethyst glass, and as the starting material for production of other manganese compounds (EPA 1984a; HSDB 1989; NAS 1973; Venugopal and Luckey 1978). Manganese chloride is used as a precursor for other manganese compounds, as a catalyst in the chlorination of organic compounds, in animal feed to supply essential trace minerals, and in dry-cell batteries (EPA 1984a; HSDB 1989). Manganese sulfate is used in glazes and varnishes, in ceramics, fertilizers, as a fungicide, and as a nutritional supplement (EPA 1984a; HSDB 1989; Windholz 1983). Potassium permanganate is used as an oxidizing agent, a disinfectant, an anti-algal agent, for metal cleaning, tanning, bleaching, and as a preservative for fresh flowers and fruits. The organomanganese compound MMT is used as an antiknock additive in unleaded gasoline (EPA 1984a; HSDB 1989; NAS 1973), but is currently banned for this purpose in the United States (EPA 1978, 1979, 1981). No information was located on the amounts of each ‘compound used for these purposes. 4.4 DISPOSAL Disposal of waste manganese into water requires a discharge permit from the EPA (see Chapter 7), but disposal of solid wastes such as manganese metal or manganese compounds is not regulated under current federal law. Most solid manganese wastes are disposed of by being deposited on land or by being trucked to off-site disposal facilities (TRI 1989). The total amount of waste manganese disposed of in this way in 1987 was 77 million pounds (TRI 1989). No information was located regarding predicted future trends in manganese disposal. 71 5. POTENTIAL FOR HUMAN EXPOSURE 5.1 OVERVIEW Manganese is an ubiquitous constituent in the environment, occurring in soil, air, water, and food. Thus, all humans are exposed to manganese, and manganese is a normal component of the human body. Food is usually the most important route of exposure for most people, with typical daily intakes of 2.5-5 mg/day. Above-average exposures to manganese are most likely to occur in or near a factory or a waste site that releases significant amounts of manganese dust into air. Manganese is also released into air by combustion of unleaded gasoline which contains manganese as an anti-knock ingredient. Since these releases are particulate in nature, the fate and transport of the particles are determined mainly by the wind and the size and density of the particles. Some manganese compounds are readily soluble, so significant exposures can also occur by ingestion of contaminated drinking water. However, manganese in surface water may oxidize or adsorb to sediment particles and settle out. Manganese in soil can migrate as particulate matter in air or water, or soluble compounds may be dissolved by water and leach from the soil. The extent of leaching is determined mainly by the characteristics of the soil, and is highly variable. Available data indicate the manganese is detectable in soil and water at nearly all NPL sites and other waste sites. In some cases this is probably due to natural levels of manganese rather than to disposal of manganese wastes, but at some sites the levels are significantly higher-than-average. Figure 5-1 shows the frequency of 145 NPL sites in states where manganese is considered to be of possible concern (View 1989). In addition, manganese is a chemical of concern at 2 NPL sites in the Commonwealth of Puerto Rico, and at 1 site in the U.S. Territory of Guam. As more sites are evaluated by the EPA, the number of sites may change. 5.2 RELEASES TO THE ENVIRONMENT Industrial manufacturers, processors, and users of manganese and manganese compounds are required to report the quantities of these substances released to environmental media annually (EPA 1988a). Table 5-1 lists the amounts of manganese released to each medium in each state in 1987 (TRI 1989). The TRI should be used with caution since the 1987 data represent first-time reporting of estimated releases by these facilities. Only certain types of facilities were required to report. This is not an exhaustive list. Additional releases of manganese to the environment occur from natural sources and from processes such as combustion of fossil fuel, incineration of wastes, or cement production (EPA 1985c, 1985d). Quantitative information on releases of manganese to specific environmental media are discussed below. FIGURE 5-1. FREQUENCY OF NPL SITES WITH MANGANESE CONTAMINATION * FREQUENCY BEEEH 1+ TO 2 SITES BEER 3 TO 4 SITES 6 TO 7 SITES I oc 12 SITES ¥ Derived from View 1989 'S HANSOdXd NVWAH ¥0d TVILNILOd CL Releases to the Environment from Facilities That Manufacture or Process Manganese and Compounds® TABLE 5-1. Range of reported amounts released in thousands of pounds” Off-site of No. POTW® waste transfer Total Environment® Underground facil- ities transfer Water Land injection Air State® 5. 0 0-267 0-124 0 0-349.8 0.3-0.3 0-3. 0 0-301 0-0 0-0 0 0-41.9 No Data 0.3-0.3 0-10.5 0-1 23dE3 73 POTENTIAL FOR 0-108 0-26 0-4 0-2 0-8 CA 27 co CT 0-0.1 0-4 0-1,725 0-690.1 30.5-1,038 0=1,717 0-688.1 0-28 0-3 0-0 0-0 10 13 0-21.8 0-18 0-2 0-549.4 0-1,038 0-0 0-0 DE FL 0-0 0-0 0-0 18 16 35 0-2 GA 0-67 0-26 0-26 180.3-180.3 0-11.3 IA ID IL IN Ks 0-181.5 0-599.1 .3 0-0 0-1,126 0-1,100 0-9 0-30 0-590 0-11.9 0-797 52 44 HUMAN EXPOSURE 0-11,010 0-1.8 0-201 0-11,000 0-173.6 0-500 0-0 0-65.2 0-27.2 0-0 0-218 0-510.2 23 0-48 KY = . wn — non. 0 N ~ 0 ~N =o non rr © ooo oo o «oo For oo oo ~ un om = © +r fs NM + ON rrr - O O ©O o ™ : n © O N Oo or © OO Oo oo wv © o © . oO ™ OO =H rr oO OO Oo Oo 4 0 0-85.5 5 388% 0~2,150 0-328.3 0-1 0-3.8 0-9 0-0 0-0 0-328.1 43 MI 0-61 0-17 0-13 0-25.9 0.1-4,900 20 0-25.9 MO 0-3,800 0-23 0-2,300 0-21.9 11 MS 0-102.3 0-4 0-10.6 0-0 0-0 0-6 20 NC ND 0-3 0-0 0-2 0-0 0-2 10 NE NH NJ 0-313 0-366 0-0 0-2 28 0-32.2 0.3-0.3 8.1-68 0-0 0.1-67 gE 0-430 0-124 0-124.6 0-62 31 0-75 NY TABLE 5-1 (Continued) Range of reported amounts released in thousands of pounds’ No. Off-site facil- Underground Total waste State! ities Air injection Water Land Environment® transfer OH 105 0-34. 0-0 0-8.6 0-5,800 0-5,800 0-2,283 OK 13 0-10 0-0 0-0.3 0-14 0-19.8 0-14 OR 12 0-13 0-0 0-0 0-5.5 0~13.9 0-140 PA 97 0-15. 0-0 0-57.8 0-3,500 0-3,547 0-2,100 PR 2 0-0 0-0 0-0 0-0 0-0 0-0.5 RI 2 .5-28 0-0 0-0 0-0 0.5-28 0-30 SC 25 0-6. 0-0 0-78 0-290 0-296.5 0-190 SD 1 .5-0. 0-0 0-0 0-0 0.5-0.5 0-0 TN 27 0-68.2 0-6,200 0-22 0-174.5 0-6,200 0-0.8 0-1,472 TX 48 0-29.8 0-0 0-28.2 0-900 0-929.8 0-1. 0-85 uT 4 0-0. 0-0 0-0 0-1,269 0-1,269 0-0 0-0 VA 18 0-1. 0-0 0-0.3 0-15.3 0-15.3 0-1. 0-32.7 vT 1 «3-0. 0-0 0-0 0-0 0.3-0.3 0-0 .1-0.1 WA 23 0-1 0-0 0-0.3 0-2.1 0-2.8 0-0. 0-163.6 WI 47 0-35. 0-0.3 0-3.1 0-190 0-225.7 0-5. 0-840 wv 12 0-20.3 0-0 0-54.5 0-20 0-73.4 0-2. 0-353 TRI 1989 "Data in TRI are maximum amounts released by each facility. hundred pounds, except those quantities >1 million pounds which have been rounded to the nearest thousand pounds. ‘Publicly owned treatment works Post office state abbreviation The sum of all releases of the chemical to air, land, water, and underground injection wells by a given facility. Quantities reported here have been rounded to the nearest 'S HINSOdXd NVWAH ¥dOod TVILNALOd ZA 75 5. POTENTIAL FOR HUMAN EXPOSURE 5.2.1 Air The main sources of manganese release to air are industrial emissions, combustion of fossil fuels, and reentrainment of manganese-containing soils (Anderson 1983; EPA 1984a, 1985c, 1985d, 1987a; Lioy 1983). The principal sources of industrial emissions are ferroalloy production and iron and steel foundries, and the principal sources of combustion emissions are power plants and coke ovens (Anderson 1983; EPA 1985c, 1985d). Total emissions to air from anthropogenic sources in the United States were estimated to be 36 million pounds in 1978, with about 80% (29 million pounds) from industrial facilities and 20% (7 million pounds) from fossil fuel combustion (Anderson 1983). Air emissions reported by industrial sources for 1987 total 2.7 million pounds (TRI 1989). The number of emitting facilities in each state and the range of their emission rates are shown in Table 5-1. Total emissions to air in North Carolina were estimated to be 15,700 pounds/year (NCDEHNR 1990). Air erosion of dusts and soils is also an important atmospheric source of manganese (EPA 1984a), but no quantitative estimates of manganese release to air from this source were located. Volcanic eruptions may also release manganese to the atmosphere (Schroeder et al. 1987). Methylcyclopentadienyl manganese tricarbonyl (MMT) is a gasoline additive which was previously used in unleaded gasoline in the United States, and combustion of gasoline containing MMT may have contributed to urban air manganese levels. Analysis of manganese levels in air suggested that vehicular emissions contributed an average of 13 ng manganese/m® in southern California, while vehicular emissions were only about 3 ng/m’ in central and northern California (Davis et al. 1988). It has been estimated that if MMT were used in all gasoline, urban air manganese levels would be increased by about 50 ng/m* (Cooper 1984; Ter Haar et al. 1975). However, this additive was banned for use in unleaded gasoline by EPA due to its detrimental effect on catalytic converters (causing increased hydrocarbon emissions) (EPA 1978, 1979, 1981). 5.2.2 Water Manganese may be released to water by discharge from industrial facilities, or as leachate from landfills and soil (EPA 1984a; Francis and White 1987; Levins et al. 1979; TRI 1989). Reported industrial discharges to surface waters, transfers to public sewage, and underground injection (releases to groundwater) for 1987 totalled 2.0 million, 0.7 million, and 8.5 million pounds, respectively (TRI 1989). Manganese has been detected in both surface water and groundwater at more than 95% of hazardous waste sites for which data are included in the Contract Laboratory Program (CLP) Statistical Database (CLPSD 1986). Note that the CLP Statistical Database includes data from both NPL and non-NPL sites. The frequency of detection at NPL sites was 97% (CLPSD 1986). The geometric mean manganese concentrations were about 200 ug/L in both surface water and groundwater at NPL sites and non-NPL sites. Based on comparison to 76 5. POTENTIAL FOR HUMAN EXPOSURE typical background levels of manganese in surface water or groundwater (see Section 5.4.2), it seems likely that some waste sites where manganese is detected contain only natural levels. However, in a number of cases, high levels (in excess of 1,000 pg/L) have been detected (View 1989), indicating that manganese wastes may lead to significant contamination of water at some sites. For example, at one site in Ohio where "heavy metals" had been disposed, manganese concentrations up to 1,900 ug/L were found in on-site wells (Cooper and Istok 1988). Levels in water at two NPL sites in Missouri ranged from 9 to 3,700 ppm (MDNR 1990). No information is available on the method used to determine these values, so it is not clear if the data refer to total or dissolved manganese. 5.2.3 Soil Land disposal of manganese-containing wastes are the principal source of manganese releases to soil. Reported industrial releases to land in 1987 totalled 44 million pounds (TRI 1989). No other data were located on releases of manganese to soils or sediments. Manganese has been detected in soil at 99% of 455 CLPSD hazardous waste sites where it has been measured, at a geometric mean concentration of 380 mg/kg (CLPSD 1986). The detection frequency at NPL sites was 97%, with a geometric mean of 360 mg/kg. The maximum reported concentration from the CLPSD was 7,100 mg/kg (Eckel and Langley 1988). Based on comparison with average background levels of manganese in soil (see Section 5.4.3), these data indicate that manganese detected in soil at some waste sites may be natural and not the results of waste disposal. However, in some cases very high levels (in excess of 2,000 mg/kg) have been reported (View 1989), indicating that soils have been significantly contaminated by dumping. However, the exact number of such sites is not known. : 5.3 ENVIRONMENTAL FATE 5.3.1 Transport and Partitioning Elemental manganese and inorganic manganese compounds have negligible vapor pressures (see Table 3-2), but may exist in air as suspended particulate matter derived from industrial emissions or the erosion of soils. Manganese- containing particles are mainly removed from the atmosphere by gravitational settling (EPA 1984a), with large particles tending to fall out faster than small particles. The half-life of airborne particles is usually on the order of days, depending on the size of the particle and atmospheric conditions (Nriagu 1979). Removal by washout mechanisms such as rain may also occur, but is less important in removing manganese from the atmosphere than dry deposition (EPA 1984a; Turner et al. 1985). The transport and partitioning of manganese in water is controlled by the solubility of the specific chemical form present, which in turn is determined by pH, Eh (oxidation-reduction potential), and the characteristics of available anions. The metal may exist in water in any of four oxidation 77 5. POTENTIAL FOR HUMAN EXPOSURE states (2+, 3+, 4+, or 7+). Divalent manganese (Mn+2) predominates in most waters (pH 4-7), but may become oxidized at pH greater than 8 or 9 (EPA 1984a). The principal anion associated with Mn(+2) in water is usually carbonate (CO,?), and the concentration of manganese is limited by the relatively low solubility (65 mg/L) of MnCO, (Schaanning et al. 1988). In relatively oxidized water, the solubility of Mn(+2) may be controlled by manganese oxide equilibria (Ponnamperuma et al. 1969), with manganese being converted to the (+3) or (+4) valence states (Rai et al. 1986). In extremely reduced water, the fate of manganese tends to be controlled by formation of the poorly soluble sulfide (EPA 1984a). Manganese is often transported in rivers as suspended sediments. Malm et al. (1988) found that most of the manganese in a South American river was bound to suspended particles enriched with the metal from industrial sources. Manganese in water may be significantly bioconcentrated at lower trophic levels. A bioconcentration factor (BCF) relates the concentration of a chemical in plant and animal tissues to the concentration of the chemical in the water in which they live. Folsom et al. (1963) estimated that the BCF of manganese was 2,500-6,300 for phytoplankton, 300-5,500 for marine algae, 800-830 for intertidal mussels, and 35-930 for coastal fish. Similarly, Thompson et al. (1972) estimated that the BCF of manganese was 10,000-20,000 for marine and freshwater plants, 10,000-40,000 for invertebrates, and 100-600 for fish. In general, these data indicate that lower organisms such as algae have larger BCFs than higher organisms. Thus, biomagnification of manganese in the food chain does not appear to be significant (EPA 1984a). The tendency of soluble manganese compounds to adsorb to soils and sediments depends mainly on the cation exchange capacity and the organic composition of the soil (Curtin et al. 1980; Hemstock and Low 1953; Kabata- Pendias and Pendias 1984; McBride 1979; Schnitzer 1969). Baes and Sharp (1983) noted that soil adsorption constants (the ratio of the concentration in soil to the concentration in water) for Mn(+2) span five orders of magnitude, ranging from 0.2 to 10,000 mL/g, increasing as a function of the organic content and the ion exchange capacity of the soil. Thus, adsorption may be highly variable. In some cases, adsorption of manganese to soils may not be a readily reversible process. At low concentrations, manganese may be "fixed" by clays, and will not be released into solution readily (Reddy and Perkins 1976). At higher concentrations, manganese may be desorbed by ion exchange mechanisms with other ions in solution (Rai et al. 1986). For example, the discharge of waste water effluent into estuarine environments resulted in the mobilization of manganese from the bottom sediments (Helz et al. 1975; Paulson et al. 1984). The metals in the effluent may have been preferentially adsorbed resulting in the release of manganese. 78 5. POTENTIAL FOR HUMAN EXPOSURE 5.3.2 Transformation and Degradation 5.3.2.1 Air Very little information is available on atmospheric reactions of manganese (EPA 1984a). Manganese can react with sulfur dioxide and nitrogen dioxide, but the occurrence of such reactions in the atmosphere has not been demonstrated. 5.3.2.2 Water Manganese in water may undergo oxidation at high pH or Eh (see Section 5.3.1.2), and is also subject to microbial activity. For example, Mn(+2) in a lake was oxidized during summer months, and this was inhibited by a microbial poison, indicating that the oxidation was mediated by bacteria (Johnston and Kipphut 1988). The importance of microbial metabolism of manganese presumably is a function of pH, temperature, and other factors, but no data were located on this. 5.3.2.3 Soil , The oxidation state of manganese in soils and sediments may be altered by microbial activity. Geering et al. (1969) observed that Mn(+2) in suspensions of silt or clay loams from several areas of the United States was oxidized by microorganisms, leading to the precipitation of manganese minerals. Other studies (Francis 1985) have shown that bacteria and microflora can increase the mobility of manganese in coal-waste solids by increasing dissolution of manganese in sub-surface environments. 5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 5.4.1 Air Table 5-2 summarizes data collected over a period of nearly 30 years from numerous urban, nonurban, and source-dominated areas of the United States. Direct comparisons of data between time periods are complicated due to changes in sample collection and analytical methodology. However, it is clear that manganese levels tend to be higher in source-dominated and urban areas than in nonurban areas. These data also indicate that concentrations in all areas have tended to decrease over the past three decades (EPA 1984a; Kleinman et al. 1980). This is probably due primarily to installation of emissions controls in the metals industry (EPA 1984a, 1985d). A concurrent decrease in total suspended particulates (TSP) was observed in most areas. 5.4.2 Water Concentrations of manganese in surface water are usually reported as dissolved manganese, although total manganese may be a better indicator, since manganese adsorbed to suspended solids may exceed dissolved manganese in many systems (EPA 1984a; NAS 1977). In a 1962-1967 survey of U.S. surface waters, 79 5. POTENTIAL FOR HUMAN EXPOSURE TABLE 5-2. Average Levels of Manganese in Ambient Air? Concentration (ng/m?) Sampling location 1953-1957 1965-1967 1982 Nonurban 60 12 5 Urban 110 73 33 Source dominated No data 250-8,300 130-140 Adapted from EPA 1984a 80 5. POTENTIAL FOR HUMAN EXPOSURE dissolved manganese was detected in 51% of 1,577 samples, at a mean concentration of 59 ug/L. Individual values ranged from 0.3 to 3,230 ug/L. Mean concentrations for 15 different drainage basins in the United States ranged from 2.3 ug/L in the Western Great Lakes to 232 ug/L in the Ohio River drainage basin (Kopp and Kroner 1967). A more recent (1974-1981) survey of United States river waters reported a median dissolved manganese concentration of 24 pg/L in samples from 286 locations, with values ranging from less than 11 pg/L (25th percentile) to more than 51 ug/L (75th percentile) (Smith et al. 1987). Natural concentrations of manganese in seawater reportedly range from 0.4 to 10 ug/L (EPA 1984a). Mean manganese concentrations in groundwater are similar to those in surface water, although some individual samples may be considerably higher. Reported mean groundwater concentrations were 20 and 90 pg/L in an analysis of California shallow groundwater from two geologic zones (Deverel and Millard 1988). Values up to 1,300 pg/L and 9,600 pg/L have been reported in neutral and acidic groundwater, respectively (EPA 1984a). Concentrations of 9,500-18,600 pg/L have been reported in four private wells in Connecticut (CDHS 1990). It is not known whether these measurements were total or dissolved manganese. A 1962 survey of public drinking water supplies in 100 large United States cities reported 97% contained less than 100 pg/L of manganese (Durfor and Becker 1964). Similarly, a 1969 survey of 969 systems reported 91% contained less than 50 ug/L, with a mean concentration of 22 ug/L (U.S. DHEW 1970). Several other studies reported similar manganese concentrations, with mean values ranging from 4 to 32 pg/L (EPA 1984a; NAS 1980a). 5.4.3 Soil Manganese comprises about 0.1% of the earth’s crust (Graedel 1978; NAS 1973), and manganese occurs naturally in virtually all soils. Average natural ("background") levels of manganese in soils range from around 40 to 900 mg/kg, with an estimated mean background concentration of 330 mg/kg (Cooper 1984; Eckel and Langley 1988; EPA 1985c; Rope et al. 1988; Schroeder et al. 1987). The maximum value reported was 7,000 mg/kg (Eckel and Langley 1988). 5.4.4 Other Environmental Media Manganese is a natural component of most foods. A summary of mean manganese concentrations in 234 foods analyzed by the U.S. Food and Drug Administration (FDA) is presented in Table 5-3. The highest manganese concentrations (up to 40 ppm) are found in nuts and grains, with lower levels (up to 4 ppm) found in milk products, meats, fish, and eggs. Collipp et al. (1983) report that concentrations of manganese in infant formulas range from 34 to 1,000 ppb, compared to concentrations of 10 ppb in human milk and 30 ppb in cow's milk. 81 5. POTENTIAL FOR HUMAN EXPOSURE TABLE 5-3. Manganese Concentrations in Selected Foods® Range of mean Type of food concentrations (ppm) Nuts and nut products 18.21-46.83 Grains and grain products 0.42-40.70 Legumes 2.24-6.73 Fruits 0.20-10.38 Fruit juices and drinks 0.05-11.47 Vegetables and vegetable products 0.42-6.64 Desserts 0.04-7.98 Infant foods 0.17-4.83 Meat, poultry, fish, and eggs 0.10-3.99 Mixed dishes 0.69-2.98 Condiments, fats, and sweeteners 0.04-1.45 Beverages (including tea) 0.00-2.09 Soups 0.19-0.65 Milk and milk products 0.02-0.49 3pdapted from Pennington et al. 1986 82 5. POTENTIAL FOR HUMAN EXPOSURE 5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE Typical daily human exposure levels to manganese from water, air, and food are summarized in Table 5-4 (EPA 1984a). As the table illustrates, the most significant exposure for the general population is from food, with an average ingestion rate of 3.8 mg/day (EPA 1984a). Other estimates of daily intake for adults range from 2.0 to 8.8 mg (EPA 1984a; NAS 1977; Patterson et al. 1984; Pennington et al. 1986; WHO 1984a). Even though gastrointestinal absorption of manganese is low (3%-5%), oral exposure is also the primary source of absorbed manganese (Table 5-4). Manganese intake among individuals varies greatly, depending upon dietary habits. For example, an average cup of tea may contain 0.4-1.3 mg of manganese (Pennington et al. 1986; Schroeder et al. 1966). Thus, an individual consuming 3 cups of tea per day might receive up to 4 mg/day from this source alone, doubling the average intake from other dietary sources. The Food and Nutrition Board of the National Research Council estimated the adequate and safe intake of manganese for adults at 2.5-5 mg/day (NAS 1980b). It is possible that a significant proportion of Americans, especially females, are not consuming sufficient manganese (NAS 1980a; Pennington et al. 1986), although no cases of manganese deficiency have ever been documented in humans. However, infants may be ingesting more than the estimated safe and adequate dose of 0.7-1.0 mg/day for their age group (Pennington et al. 1986), due to high manganese levels in prepared infant foods (Table 5-3) and formulas (Collipp et al. 1983). In the workplace, exposure to manganese is most likely to occur by inhalation of manganese fumes or manganese-containing dusts. This is a concern mainly in the ferromanganese, iron and steel, dry cell battery, and welding industries (WHO 1986). Exposure may also occur during manganese mining and ore processing, although manganese is not currently mined in the United States. In 1980, it was estimated that about 300 workers in the United States were exposed to pure manganese, and about 630,000 workers to other forms of manganese (NOES 1989). Manganese concentrations in workplace air have been monitored in industrial settings in several European countries. Concentrations of 1.5-450 mg manganese/m> have been reported in manganese mines (EPA 1984a), 0.30-20 mg manganese/m’ in ferroalloy production facilities (Saric et al. 1977), and 3-18 mg manganese/m’ in a dry battery facility (Emara et al. 1971). No data were located on current occupational exposure levels to manganese in the United States, but it is assumed that exposure levels do not exceed the OSHA time-weighted average Permissible Exposure Limit (PEL) of 1 mg manganese/m> (see Table 7-1). Assuming inhalation of 10 m® of air during an average work day, maximum occupational exposure would be 10 mg manganese/day. This exceeds the average exposure from ambient air by more than a factor of 10* and is about 2.5 times the average exposure from the diet. Thus, for workers in industries using manganese, the major route of exposure may be inhalation from workplace air, rather than ingestion of food. 83 5. POTENTIAL FOR HUMAN EXPOSURE TABLE 5-4. Summary of Typical Human Exposure to Manganese? Exposure medium Parameter Water Air Food Typical concentration 4 pg/L 0.023 ug/m’ 1.28 pg/calorie in medium Assumed daily intake of 2 L 20 m? 3,000 calories medium by 70-kg adult Estimated average daily 8 ug 0.46 ug’ 3,800 ug intake by 70-kg adult Assumed absorption 0.03¢ 1 0.03°¢ fraction Approximate absorbed 0.24 pg 0.46 pug 114 upg dose 3Adapted from EPA 1984a bAssumes 100% deposition in the lungs. °See Section 2.3.1.2 dNo data; assumed value 84 5. POTENTIAL FOR HUMAN EXPOSURE 5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES As discussed in Section 5.5, workers in industries using or producing manganese are mostly likely to have high exposure to manganese, primarily by inhalation of manganese dusts in workplace air. Populations living in the vicinity of ferromanganese or iron and steel manufacturing facilities, coal- fired power plants, or hazardous waste sites may also be exposed to elevated manganese particulate matter in air, although this exposure is likely to be much lower than in the workplace. Populations living in regions of natural manganese ore deposits may be exposed to above-average levels in soil or water. Children are especially likely to receive above-average doses from manganese-containing soils, since the intake of soil by children (mainly through hand-to-mouth contact) is higher than for adults (Calabrese et al. 1989). People ingesting large amounts of foods high in manganese also have a potential for above-average exposure. Included in this group would be vegetarians, who ingest a larger proportion of grains, legumes and nuts in their diets than the average United States population, and heavy tea drinkers. 5.7 ADEQUACY OF THE DATABASE Section 104(i) (5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate information on the health effects of manganese is available. Where adequate information is not available, ATSDR, in conjunction with the NTP, is required to assure the initiation of a program of research designed to determine the health effects (and techniques for developing methods to determine such health effects) of manganese. The following categories of possible data needs have been identified by a joint team of scientists from ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that, if met, would reduce or eliminate the uncertainties of human health assessment. In the future, the identified data needs will be evaluated and prioritized, and a substance-specific research agenda will be proposed. 5.7.1 Data Needs Physical and Chemical Properties. The fundamental physical and chemical properties of manganese and manganese compounds are known (see Table 3-2), and additional research does not appear necessary. Production, Import/Export, Use, and Disposal. Information is available on U.S. import of manganese ore and production of ferromanganese (HSDB 1989; U.S. Bureau of Mines 1989; TRI 1989), but more recent data would be valuable. 85 5. POTENTIAL FOR HUMAN EXPOSURE It is clear that most manganese is used in steel production, but detailed information on the amount and type of manganese compounds used in various other products was not located, and would be helpful in evaluating possible consumer exposures. According to the Emergency Planning and Community Right-to-Know Act of 1986, 42 U.S.C. Section 11023, industries are required to submit chemical release and off-site transfer information to the EPA. The Toxics Release Inventory (TRI), which contains this information for 1987, became available in May of 1989. This database will be updated yearly and should provide a list of industrial production facilities and emissions. Data from the TRI database provide valuable information on the amounts of manganese released to different environmental media (air, soil, water) each year, although details on the chemical form and physical state of the waste materials are not included. These disposal practices are not regulated under current federal law. Environmental Fate. The partitioning of manganese between water and soil can be fairly-well predicted using thermodynamic equilibrium concepts, if soil-specific information is available (Baes and Sharp 1983; Rai et al. 1986). However, the kinetics of these reactions have not been studied in detail. Kinetic studies could help determine the residence time of manganese released into water or soil. The fate of manganese particles released into air is determined by the particle size, and the direction and distance of particle transport at a site can be predicted from meteorological data and particle size data (EPA 1984a; Nriagu 1979). Transport of manganese in water is determined mainly by the solubility of the manganese compounds present, although suspended particles may also be transported in flowing waters (EPA 1984a; Schaunning et al. 1988). The primary transformations which manganese undergoes in the environment are oxidation/reduction reactions (EPA 1984a; Rai et al. 1986). Reactions of manganese with airborne oxidants have not been studied. Information on the rate and extent of such reactions would be helpful in understanding the fate of atmospheric releases. Transformation of manganese in water or soil is dependent mainly on Eh, pH, and available counter ions (EPA 1984a). In some soils, manganese may also be oxidized by bacteria (Geering et al. 1969; Johnston and Kipphut 1988). Further field work on the environmental factors that determine fate and transport of manganese in soils and water would be helpful in improving the ability to predict future exposures near waste sites. Bioavailability from Environmental Media. Manganese is known to be absorbed following inhalation or oral exposure, but dermal exposure is not considered to be significant (Mena et al. 1969; Pollack et al. 1965). The uptake of manganese from air, food, milk, and water has been studied (Davidsson et al. 1988, 1989). However, absorption from soil has not been investigated. In view of the potential for tight binding of manganese to some soil types, studies on this subject would be valuable in evaluating risk to humans who may ingest contaminated soils near waste sites. 86 5. POTENTIAL FOR HUMAN EXPOSURE Food Chain Bioaccumulation. It has been established that while lower organisms (plankton, aquatic plants, some fish) can significantly bioconcentrate manganese, higher organisms (including humans) tend to maintain manganese homeostasis (EPA 1984a; Folsom et al. 1963; Thompson et al. 1972). This indicates that the potential for biomagnification of manganese from lower trophic levels to higher ones is low, and it does not appear that additional research in this area is essential at this time. Exposure Levels in Environmental Media. Manganese levels have been monitored in all environmental media, including air, water, soil, and food (EPA 1984a; NAS 1980a; Pennington et al. 1986). The EPA has estimated average human intake levels of manganese from water, air, and food (EPA 1984a). These estimates were based mainly on monitoring data from the 1960s and 1970s, so more recent data would be valuable in identifying any trends in environmental contamination. Data on manganese levels in the vicinity of waste sites are available from CLPSD (1986), including data specifically for NPL sites. These data suggest that levels of manganese in the environment around some waste sites are generally similar to typical background levels, but that a number of sites are significantly above background. More specific data on levels in the environment around those particular sites where manganese is believed to have been dumped would be helpful in determining the extent of exposure levels around such waste sites. In particular, data on the concentration of manganese in air around waste sites would be valuable in assessing the potential significance of this exposure pathway. Exposure Levels in Humans. Manganese is a normal component of human tissues and fluids (Sumino et al. 1975; Tipton and Cook 1963). Increased average levels of manganese have been detected in blood and urine of populations exposed to high concentrations of manganese in the workplace (Roels et al. 1987b), but no similar data are available for populations surrounding waste sites. Surveys of manganese levels in blood or urine of populations living near waste sites could be useful in identifying groups with above-average levels of manganese exposure. However, due to the variability in these values, it is not likely that such data would be helpful in identifying individuals with above average exposures. Exposure Registries. No exposure registries for manganese were located. This compound is not currently one of the compounds for which a subregistry has been established in the National Exposure Registry. The compound will be considered in the future when chemical selection is made for subregistries to be established. The information that is amassed in the National Exposure Registry facilitates the epidemiological research needed to assess adverse health outcomes that may be related to the exposure to this compound. 87 5. POTENTIAL FOR HUMAN EXPOSURE 5.7.2 On-going Studies On-going remedial investigations and feasibility studies at NPL sites contaminated with manganese will add to the available database on exposure levels in environmental media and exposure levels in humans. No other information was located on any on-going studies on the fate, transport, or potential for human exposure to manganese. 89 6. ANALYTICAL METHODS The purpose of this chapter is to describe the analytical methods that are available for detecting and/or measuring and monitoring manganese in environmental media and in biological samples. The intent is not to provide an exhaustive list of analytical methods that could be used to detect and quantify manganese. Rather, the intention is to identify well-established methods that are used as the standard methods of analysis. Many of the analytical methods used to detect manganese in environmental samples are the standardized protocols developed by federal agencies such as EPA and the National Institute for Occupational Safety and Health (NIOSH). Other methods presented in this chapter are those that are approved by groups such as the Association of Official Analytical Chemists (AOAC) and the American Public Health Association (APHA). Additionally, analytical methods are included that refine previously used methods to obtain lower detection limits, and/or to improve accuracy and precision. Flame atomic absorption analysis is the most straightforward and widely used method for determining manganese (Tsalev 1983). In this method, a solution containing manganese is introduced into a flame, and the concentration of manganese is determined from the intensity of the color at 279.5 nm. Furnace atomic absorption analysis is often used for very low analyte levels (Baruthio et al. 1988), and inductively coupled plasma atomic emission analysis is frequently employed for multianalyte analyses that include manganese. Other methods for measuring manganese include spectrophotometry, mass spectrometry, neutron activation analysis, and x-ray fluorimetry. It is important to note that none of these methods distinguish between different valence states of manganese, or between different manganese compounds. Thus, monitoring data on manganese is nearly always available only as total manganese present. 6.1 BIOLOGICAL MATERIALS Normally, determination of manganese in biological materials requires digestion of the organic matrix prior to analysis. For tissue samples or feces, this is usually done by treatment with an oxidizing acid mixture such as 3:1:1 (v/v/v) nitric:perchloric:sulfuric acid mixture (Kneip and Crable 1988a). Fluid samples such as blood or urine, may be digested in the same way, or manganese can be extracted by an ion exchange resin or by chelating agents such as cupferon in methylisobutylketone. Table 6-1 summarizes some of the methods used for sample preparation and analysis of manganese in biological materials. It is important to note that special care is needed to avoid contamination of biological materials with exogenous manganese (Tsalev 1983; Versieck et al. 1988). TABLE 6-1. Analytical Methods for Determining Manganese in Biological Materials Sample detection Percent Sample matrix Preparation method Analytical method limit recovery Reference Urine Extraction into methylisobutyl- AAS (furnace <1 pg/L? No data Baselt 1988 ketone as the cupferon chelate technique) Urine Extract with resin, ash resin ICP/AES 0.1 pg 100+10% NIOSH 1984d Blood Acid digestion ICP/AES 1 pg/dL 984+2.1% Kneip and Crable 1988a Blood Digestion in oxidizing acid ICP/AES 1 pg/100g 98+2.1% NIOSH 1984c Tissue Digestion in oxidizing acid ICP/AES 0.2 pglg 98+2.1% NIOSH 1984c Tissue Acid digestion ICP/AES 0.2 pglg 104+5.6% Kneip and Crable 1988a Feces Dry at 110°, ash at 550°, AAS (flame <1 pglg 102+7% Friedman dissolve in nitric acid technique) et al. 1987 Hair Digestion in concentrated Flameless <0.2 pgl/g No data Collipp nitric:perchloric acid AAS et al. 1983 (3:1) mixture Estimated from sensitivity and linearity data. AAS = atomic absorption spectroscopy; ICP/AES = inductively coupled plasma atomic emission spectroscopy ‘9 SAOHLIW TVDILATVNV 06 91 6. ANALYTICAL METHODS 6.2 ENVIRONMENTAL SAMPLES Manganese in air exists as particulate matter, so sampling is done by drawing air through a filter in order to collect the suspended particles. A variety of filter types (glass fibers, cellulose acetate) and sampling devices (low volume, high volume, dichotomous) are available, depending on the particle sizes of concern and the concentration range of interest. In some cases, material on the filter may be analyzed directly (e.g., by x-ray fluorescence), or the filter may be digested by ashing in acid prior to analysis. In general, sensitivity is dependent on the volume of air drawn through the filter prior to analysis. Water may either be analyzed directly, or, if the concentration of manganese is low, a concentration step (evaporation, extraction, binding to a resin) may be employed. In all cases, acid is added to the sample to prevent precipitation of manganese. Determination of manganese levels in soils, sludges, or other solid wastes requires an acid extraction/digestion step prior to analysis., The details vary with the specific characteristics of the sample, but usually treatment will involve (a) heating in nitric acid, (b) oxidation with hydrogen peroxide, and (c) filtration and/or centrifugation to remove insoluble matter. Table 6-2 summarizes some common methods for the determination of manganese in various types of environmental media. 6.3 ADEQUACY OF THE DATABASE Section 104(i) (5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate information on the health effects of manganese is available. Where adequate information is not available, ATSDR, in conjunction with the NTP, is required to assure the initiation of a program of research designed to determine the health effects (and techniques for developing methods to determine such health effects) of manganese. The following categories of possible data needs have been identified by a joint team of scientists from ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that, if met, would reduce or eliminate the uncertainties of human health assessment. In the future, the identified data needs will be evaluated and prioritized, and a substance-specific research agenda will be proposed. TABLE 6-2. Analytical Methods for Determining Manganese in Environmental Samples Sample detection Percent Sample matrix Preparation method Analytical method limit recovery Reference Air Collection on filter, XRF 2 pg/sample No data NIOSH 1984a direct analysis Air Collection on filter, ICP/AES 1 pg/sample 847-937 NIOSH 1984b acid digestion (5 pg/m?) Water Acidify with nitric acid AAS (furnace 0.2 pg/L No data EPA 1983b technique) Water Acidify with nitric acid AAS (flame) 2 pg/L No data Taylor 1982 AAS (furnace) 0.01 pg/L No data ICP/AES 1 pg/L No data Water Acidify with nitric acid AAS (direct 10 pg/L 100+6% APHA 1985a aspiration) Water Adjust pH to 2-4, extract AAS (direct <10 pg/L No data APHA 1985b with APDC into MIBK aspiration) Water Acidify with nitric acid AAS (furnace 0.2 pg/L No data APHA 1985c technique) Water Acidify with nitric acid ICP/AES 2 pg/L No data APHA 1985d Water Acidify with nitric acid AAS (direct 10 pg/L 100+2%* EPA 1983a aspiration) Water Acidify, oxidize Colormetric 50 pg/L 100+26% APHA 1985e Water and wastes Acid digestion ICP/AES 2 pg/L 100+6% EPA 1982 Water and wastes Acid digestion AAS 10 pg/L 100+2%? EPA 1986¢ Water and wastes Acid digestion ICP/AES 2 pg/L 93161 EPA 1986b Sediments, Acid digestion, oxidation, AAS, Variable, 93+6% EPA 1986a, sludges, soils filtration/centrifugation ICP/AES depending 1986b on matrix ‘Percent recovery at manganese concentration greater than 80 pg/L. were greater than 120%. AAS = atomic absorption spectrometry; APDC = ammonium pyrrolidine dithiocarbamate; ICP/AES atomic emission spectroscopy; MIBK = methyl isobutyl ketone; XRF = x-ray fluorescence At lower concentrations (10-20 pg/L) percent recoveries inductively coupled plasma ‘9 SAOHIAW TVOILATVNV 6 93 6. ANALYTICAL METHODS 6.3.1 Data Needs Methods for Determining Biomarkers of Exposure and Effect. Sensitive and selective methods are available for the detection and quantitative measurement of manganese in blood, urine, hair, feces, and tissues (Baselt 1988; Collipp et al. 1983; Friedman et al. 1987; Kneip and Crable 1988a; NIOSH 1984c, 1984d). Since levels in biological samples are generally rather low, sample contamination with exogenous manganese can sometimes occur (Tsalev 1983; Versieck et al. 1988). Development of standard methods for limiting this problem would be useful. As discussed in Section 2.5.1, measurement of average manganese concentrations in these materials has proved useful in comparing groups of occupationally exposed people to nonexposed people (Roels et al. 1987b), but has not been especially valuable in evaluating human exposure in individuals (Rehnberg et al. 1982). This is due to the inherent variability in intake levels and toxicokinetics of manganese in humans, rather than a limitation in the analytical methods for manganese. Development of noninvasive methods for measuring whole-body or tissue-specific manganese burdens would be valuable in estimating human exposure levels, but would be limited by the same considerations of individual variability that limit existing methods. No reliable biomarkers of manganese effect are known. Biochemical changes such as altered blood or urinary levels of steroids, neuro- transmitters, or their metabolites are plausible biomarkers of exposure, but these have not been thoroughly investigated. Methods exist for the analysis of these biochemicals, and further work to improve sensitivity or specificity does not seem warranted unless the utility of this approach is established. Methods for Determining Parent Compounds and Degradation Products in Environmental Media. All humans are exposed to manganese, primarily through food (EPA 1984a). Near a waste site or a factory that permitted release of manganese, humans could receive above-average exposure by inhaling manganese particles in air, or by ingesting manganese that has entered drinking water, soil, or food. Analytical methods exist for the analysis of manganese in all of these media, and the sensitivity of these methods is more than enough to detect levels of potential human health concern (APHA 1985a, 1985b, 1985c, 1985d, 1985e; EPA 1982, 1986b, 1986c; NIOSH 1984a, 1984b). Therefore, further efforts in the area do not appear to be essential. 6.3.2 On-going Studies No information was located regarding on-going research on methods for analysis of manganese in biological materials or environmental samples. 95 7. REGULATIONS AND ADVISORIES Because of its potential to cause adverse health effects in exposed people, a number of regulations and guidelines have been established for manganese by various national and state agencies. These values are summarized in Table 7-1. The EPA has derived a chronic oral reference dose (RfD) of 0.1 mg/kg/day for manganese (IRIS 1991). This value is equal to the average daily intake of manganese in the diet (10 mg/day) that is considered adequate and safe. The RfD was derived assuming an average body weight of 70 kg. An uncertainty factor was not employed, because (a) the information used to determine the RfD manganese was taken from many large populations, (b) humans exert an efficient homeostatic control over manganese such that body burdens are kept constant with variations in diet, (c) there are no subpopulations which are believed to be more sensitive to manganese at this level, and (d) manganese is an essential element, being required for normal human growth and maintenance of health. The EPA has also derived a chronic inhalation reference concentration (RfC) of 0.4 pg/m? for manganese (IRIS 1991). This value is based on the LOAEL of 1 mg/m’ identified in the study by Roels et al. (1987a). EPA calculated the RfC by dividing by an uncertainty factor of 900 (a factor of 10 for use of a LOAEL, a factor of 10 for human variability, a factor of 3 for less than lifetime exposure, and another factor of 3 for the possibility that exposure levels measured at the time of the study may have been higher than in the past when most exposures occurred). The estimated breathing rate in the exposed workers was assumed to be 10 m?/workday. 96 7. REGULATIONS AND ADVISORIES TABLE 7-1. Regulations and Guidelines Applicable to Manganese Agency Description Information References INTERNATIONAL WHO Guideline value in drinking water 0.1 mg/L WHO 1984a for aesthetic quality Recommended exposure limit in 0.3 mg/m’ WHO 1986 workplace air - respirable manganese particles Recommended air quality guideline 1 ug/m? WHO 1987 (annual average) NATIONAL Regulations: a. Air: EPA OAQPS Ban on use of methylcyclopentadienyl Yes EPA 1978, 1979, manganese tricarbonyl as a fuel 1981 additive in unleaded gasoline OSHA PEL TWA OSHA 1989 Manganese fume, as manganese 1 mg/m’ (29 CFR Manganese cyclopentadienyl 0.1 mg/m? 1910.1000) tricarbonyl, as manganese (Table Z-1-A) Manganese tetroxide 1 mg/m’ STEL Manganese fume 3 mg/m? Ceiling Manganese compounds, as manganese 5 mg/m’ b. Water: EPA OWRS General permits under NPDES Yes 40 CFR 122, for total manganese Appendix D, Table IV c. Food: FDA Concentration in bottled water 0.05 mg/L 21 CFR 103.35 d. Other: EPA OERR Reportable quantity EPA 1989c (40 Manganese, tricarbonyl methyl- 1 1b CFR 302.4) cyclopentadienyl Potassium permanganate 100 1b EPA 1989d (40 CFR 302.4) Reportable quantity (proposed) EPA 1989c Manganese, tricarbonyl methyl- 100 lbs cyclopentadienyl Extremely Hazardous Substance TPQ EPA 1987b Manganese, tricarbonyl methyl- 100 lbs (40 CFR 355) cyclopentadienyl EPA OSW Monitor at hazardous waste Yes 40 CFR 265.92 facilities to establish groundwater quality EPA OTS Toxic chemical release reporting Yes EPA 1988a manganese; manganese compounds (40 CFR 372) 97 7. REGULATIONS AND ADVISORIES TABLE 7-1 (Continued) Agency Description Information References NATIONAL (cont.) DOJ DEA Potassium permangate ranked as Yes DOJ 1990 essential chemical in illegal drug production. Records of sales and uses required for amounts over 500 kg. Guidelines: a. Air: ACGIH TLV TWA Manganese dust and compounds, as manganese Manganese tetroxide, compound and manganese fume, as manganese Manganese cyclopentadienyl tricarbonyl, as manganese 2-Methylcyclopentadienyl manganese tricarbonyl, as manganese STEL Manganese fume b. Water: EPA ODW Secondary MCL for aesthetic quality c. Other: EPA Carcinogenic Classification RfD (oral) RfC STATE Regulations and Guidelines: a. Air: Acceptable ambient air concentrations Manganese Connecticut Nevada North Carolina North Dakota Pennsylvania Rhode Island South Dakota Vermont Virginia Manganese cyclopentadienyl tricarbonyl Connecticut Nevada North Carolina North Dakota Virginia Manganese tetroxide Connecticut Nevada North Carolina North Dakota Virginia ACGIH 1986, 1988 5 mg/m’ 1 mg/m? 0.1 mg/m’ 0.2 mg/m’ 3 mg/m’ 0.05 mg/L 40 CFR 143.3 Group D? IRIS 1991 0.1 mg/kg/day 4x10°* mg/m’ NATICH 1989" 20.0 pg/m’ (8 hr) 1.19E-1 mg/m’ (8 hr) 3.10E-2 mg/m’ (24 hr) 5.0E-2 mg/m? (1 hr) NDSDHCL 1990 24 pg/m® (annual) 2.0 pug/m® (1 hr) 20 pg/m® (8 hr) 119 pg/m® (annual) 17.0 pug/m® (24 hr) 2.0 ug/m® (8 hr) 1.0 pug/m’ (8 hr) 0.6 ug/m*> (24 hr) 1.0 pg/m’ (8 hr) NDSDHCL 1990 1.60 ug/m® (24 hr) 20 pg/m® (8 hr) 0.24 pg/m*® (8 hr) 6.0 pug/m® (24 hr) 10 pug/m® (8 hr) 16 pg/m® (24 hr) 98 7. REGULATIONS AND ADVISORIES TABLE 7-1 (Continued) Agency Description Information References STATE (cont.) b. Water: Drinking water quality standards FSTRAC 1988 Illinois 150 ug/L® Kansas 50 ug/L New Mexico 200 ug/L NMHED 1990 Wisconsin 50 ug/L? WDHSS 1990 Group D = not classifiable as to human carcinogenicity. "All data on state regulations and guidelines from NATICH 1989 unless noted otherwise. ‘Only for communities serving less than or 1,000 persons or less than or 300 service connections. 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Accumulation of Cu, Zn, Mn, Cr and Co in the human liver before birth. Biol Neonate 20:360-367. *Windholz M, ed. 1983. The Merck index: An encyclopedia of chemicals, drugs and biologicals. 10th ed. Rahway, NJ: Merck and Company, Inc., 816-818. Witschi HP, Hakkinen PJ, Kehrer JP. 1981. Modification of lung tumor development in A/J mice. Toxicology 21:37-45. Witzleben CL, Boyer JL, Ng OC. 1987. Manganese-bilirubin cholestasis. Further studies in pathogenesis. Lab Invest 56:151-154. *Wong PK. 1988. Mutagenicity of heavy metals. Bull Environ Contam Toxicol 40:597-603. %*Yamada M, Ohno S, Okayasu I, et al. 1986. Chronic manganese poisoning: A neuropathological study with determination of manganese distribution in the brain. Acta Neuropathol (Berl) 70:273-278. Yong VW, Perry TL, Godolphin WJ, et al. 1986. Chronic organic manganese administration in the rat does not damage dopaminergic nigrostriatal neurons. Neurotoxicology 7:19-24. *Zaidi SH, Dogra RK, Shanker R, et al. 1973. Experimental infective manganese pneumoconiosis in guinea pigs. Environ Res 6:287-297. *Zakour RA, Glickman BW. 1984. Metal-induced mutagenesis in the lacl gene of Escherichia coli. Mutat Res 126:9-18. Zaprianov ZK, Tsalev DL, Gheorghieva RB, et al. 1985. New toxicokinetic exposure tests based on atomic absorption analysis of toenails. I. Manganese. Proceedings of the 5th International Conference on Heavy Metals in the Environment 2:95-97. Zidenberg-Cherr S, Hurley LS, Lonnerdal B, et al. 1985. Manganese deficiency: Effects on susceptibility to ethanol toxicity in rats. J Nutr 115:460-467. Zielhuis RL, del Castilho P, Herber RF, et al. 1978. Levels of lead and other metals in human blood: Suggestive relationships, determining factors. Environ Health Perspect 25:103-109. 131 8. REFERENCES *Zlotkin SH, Buchanan BE. 1986. Manganese intakes in intravenously fed infants: Dosages and toxicity studies. Biol Trace Element Res 9:271-279. 133 9. GLOSSARY Acute Exposure -- Exposure to a chemical for a duration of 14 days or less, as specified in the Toxicological Profiles. Adsorption Coefficient (K,.) -- The ratio of the amount of a chemical adsorbed per unit weight of organic carbon in the soil or sediment to the concentration of the chemical in solution at equilibrium. Adsorption Ratio (Ky) -- The amount of a chemical adsorbed by a sediment or soil (i.e., the solid phase) divided by the amount of chemical in the solution phase, which is in equilibrium with the solid phase, at a fixed solid/solution ratio. It is generally expressed in micrograms of chemical sorbed per gram of soil or sediment. Bioconcentration Factor (BCF) -- The quotient of the concentration of a chemical in aquatic organisms at a specific time or during a discrete time period of exposure divided by the concentration in the surrounding water at the same time or during the same period. Cancer Effect Level (CEL) -- The lowest dose of chemical in a study, or group of studies, that produces significant increases in the incidence of cancer (or tumors) between the exposed population and its appropriate control. Carcinogen -- A chemical capable of inducing cancer. Ceiling Value -- A concentration of a substance that should not be exceeded, even instantaneously. Chronic Exposure -- Exposure to a chemical for 365 days or more, as specified in the Toxicological Profiles. Developmental Toxicity -- The occurrence of adverse effects on the developing organism that may result from exposure to a chemical prior to conception (either parent), during prenatal development, or postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point in the life span of the organism. Embryotoxicity and Fetotoxicity -- Any toxic effect on the conceptus as a result of prenatal exposure to a chemical; the distinguishing feature between the two terms is the stage of development during which the insult occurred. The terms, as used here, include malformations and variations, altered growth, and in utero death. EPA Health Advisory -- An estimate of acceptable drinking water levels for a chemical substance based on health effects information. A health advisory is not a legally enforceable federal standard, but serves as technical guidance to assist federal, state, and local officials. Immediately Dangerous to Life or Health (IDLH) -- The maximum environmental concentration of a contaminant from which one could escape within 30 min without any escape-impairing symptoms or irreversible health effects. 134 9. GLOSSARY Intermediate Exposure -- Exposure to a chemical for a duration of 15-364 days as specified in the Toxicological Profiles. Immunologic Toxicity -- The occurrence of adverse effects on the immune system that may result from exposure to environmental agents such as chemicals. In Vitro -- Isolated from the living organism and artificially maintained, as in a test tube. In Vivo -- Occurring within the living organism. Lethal Concentrationg,, (LC) -- The lowest concentration of a chemical in air which has been reported to have caused death in humans or animals. Lethal Concentration sg, (LCs) -- A calculated concentration of a chemical in air to which exposure for a specific length of time is expected to cause death in 50% of a defined experimental animal population. Lethal Dose ,, (LD) -- The lowest dose of a chemical introduced by a route other than inhalation that is expected to have caused death in humans or animals. Lethal Dosesgy, (LDsy) -- The dose of a chemical which has been calculated to cause death in 50% of a defined experimental animal population. Lethal Time so, (LTse) -- A calculated period of time within which a specific concentration of a chemical is expected to cause death in 50% of a defined experimental animal population. Lowest -Observed-Adverse-Effect Level (LOAEL) -- The lowest dose of chemical in a study or group of studies, that produces statistically or biologically significant increases in frequency or severity of adverse effects between the exposed population and its appropriate control. Malformations -- Permanent structural changes that may adversely affect survival, development, or function. Minimal Risk Level -- An estimate of daily human exposure to a chemical that is likely to be without an appreciable risk of deleterious effects (noncancerous) over a specified duration of exposure. Mutagen -- A substance that causes mutations. A mutation is a change in the genetic material in a body cell. Mutations can lead to birth defects, miscarriages, or cancer. Neurotoxicity -- The occurrence of adverse effects on the nervous system following exposure to chemical. 135 9. GLOSSARY No-Observed-Adverse-Effect Level (NOAEL) -- The dose of chemical at which there were no statistically or biologically significant increases in frequency or severity of adverse effects seen between the exposed population and its appropriate control. Effects may be produced at this dose, but they are not considered to be adverse. Octanol-Water Partition Coefficient (K,,) -- The equilibrium ratio of the concentrations of a chemical in n-octanol and water, in dilute solution. Permissible Exposure Limit (PEL) -- An allowable exposure level in workplace air averaged over an 8-hour shift. q;* -- The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the multistage procedure. The q;* can be used to calculate an estimate of carcinogenic potency, the incremental excess cancer risk per unit of exposure (usually ug/L for water, mg/kg/day for food, and pg/m® for air). Reference Dose (RfD) -- An estimate (with uncertainty spanning perhaps an order of magnitude) of the daily exposure of the human population to a potential hazard that is likely to be without risk of deleterious effects during a lifetime. The RfD is operationally derived from the NOAEL (from animal and human studies) by a consistent application of uncertainty factors that reflect various types of data used to estimate RfDs and an additional modifying factor, which is based on a professional judgment of the entire database on the chemical. The RfDs are not applicable to nonthreshold effects such as cancer. Reportable Quantity (RQ) -- The quantity of a hazardous substance that is considered reportable under CERCLA. Reportable quantities are: (1) 1 1b or greater or (2) for selected substances, an amount established by regulation either under CERCLA or under Sect. 311 of the Clean Water Act. Quantities are measured over a 24-hour period. Reproductive Toxicity -- The occurrence of adverse effects on the reproductive system that may result from exposure to a chemical. The toxicity may be directed to the reproductive organs and/or the related endocrine system. The manifestation of such toxicity may be noted as alterations in sexual behavior, fertility, pregnancy outcomes, or modifications in other functions that are dependent on the integrity of this system. Short-Term Exposure Limit (STEL) -- The maximum concentration to which workers can be exposed for up to 15 min continually. No more than four excursions are allowed per day, and there must be at least 60 min between exposure periods. The daily TLV-TWA may not be exceeded. Target Organ Toxicity -- This term covers a broad range of adverse effects on target organs or physiological systems (e.g., renal, cardiovascular) extending from those arising through a single limited exposure to those assumed over a lifetime of exposure to a chemical. 136 9. GLOSSARY Teratogen -- A chemical that causes structural defects that affect the development of an organism. Threshold Limit Value (TLV) -- A concentration of a substance to which most workers can be exposed without adverse effect. The TLV may be expressed as a TWA, as a STEL, or as a CL. Time-weighted Average (TWA) -- An allowable exposure concentration averaged over a normal 8-hour workday or 40-hour workweek. Toxic Dose (TDsy) -- A calculated dose of a chemical, introduced by a route other than inhalation, which is expected to cause a specific toxic effect in 50% of a defined experimental animal population. Uncertainty Factor (UF) -- A factor used in operationally deriving the RfD from experimental data. UFs are intended to account for (1) the variation in sensitivity among the members of the human population, (2) the uncertainty in extrapolating animal data to the case of human, (3) the uncertainty in extrapolating from data obtained in a study that is of less than lifetime exposure, and (4) the uncertainty in using LOAEL data rather than NOAEL data. Usually each of these factors is set equal to 10. A-1 APPENDIX A USER'S GUIDE Chapter 1 Public Health Statement This chapter of the profile is a health effects summary written in nontechnical language. Its intended audience is the general public especially people living in the vicinity of a hazardous waste site or substance release. If the Public Health Statement were removed from the rest of the document, it would still communicate to the lay public essential information about the substance. The major headings in the Public Health Statement are useful to find specific topics of concern. The topics are written in a question and answer format. The answer to each question includes a sentence that will direct the reader to chapters in the profile that will provide more information on the given topic. Chapter 2 Tables and Figures for Levels of Significant Exposure (LSE) Tables (2-1, 2-2, and 2-3) and figures (2-1 and 2-2) are used to summarize health effects by duration of exposure and endpoint and to illustrate graphically levels of exposure associated with those effects. All entries in these tables and figures represent studies that provide reliable, quantitative estimates of No-Observed-Adverse-Effect Levels (NOAELs), Lowest-Observed- Adverse-Effect Levels (LOAELs) for Less Serious and Serious health effects, or Cancer Effect Levels (CELs). In addition, these tables and figures illustrate differences in response by species, Minimal Risk Levels (MRLs) to humans for noncancer end points, and EPA's estimated range associated with an upper-bound individual lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. The LSE tables and figures can be used for a quick review of the health effects and to locate data for a specific exposure scenario. The LSE tables and figures should always be used in conjunction with the text. The legends presented below demonstrate the application of these tables and figures. A representative example of LSE Table 2-1 and Figure 2-1 are shown. The numbers in the left column of the legends correspond to the numbers in the example table and figure. LEGEND See LSE Table 2-1 (1). Route of Exposure One of the first considerations when reviewing the toxicity of a substance using these tables and figures should be the relevant and appropriate route of exposure. When sufficient data exist, (2). (3). (4). (5). (6). (7). (8). 9). A-2 APPENDIX A three LSE tables and two LSE figures are presented in the document. The three LSE tables present data on the three principal routes of exposure, i.e., inhalation, oral, and dermal (LSE Table 2-1, 2-2, and 2-3, respectively). LSE figures are limited to the inhalation (LSE Figure 2-1) and oral (LSE Figure 2-2) routes. Exposure Duration Three exposure periods: acute (14 days or less); intermediate (15 to 364 days); and chronic (365 days or more) are presented within each route of exposure. In this example, an inhalation study of intermediate duration exposure is reported. Health Effect The major categories of health effects included in LSE tables and figures are death, systemic, immunological, neurological, developmental, reproductive, and cancer. NOAELs and LOAELs can be reported in the tables and figures for all effects but cancer. Systemic effects are further defined in the "System" column of the LSE table. Key to Figure Each key number in the LSE table links study information to one or more data points using the same key number in the corresponding LSE figure. In this example, the study represented by key number 18 has been used to define a NOAEL and a Less Serious LOAEL (also see the two "18r" data points in Figure 2-1). Species The test species, whether animal or human, are identified in this column. Exposure Frequency/Duration The duration of the study and the weekly and daily exposure regimen are provided in this column. This permits comparison of NOAELs and LOAELs from different studies. In this case (key number 18), rats were exposed to [substance x] via inhalation for 13 weeks, 5 days per week, for 6 hours per day. System This column further defines the systemic effects. These systems include: respiratory, cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, and dermal/ocular. "Other" refers to any systemic effect (e.g., a decrease in body weight) not covered in these systems. In the example of key number 18, one systemic effect (respiratory) was investigated in this study. NOAEL A No-Observed-Adverse-Effect Level (NOAEL) is the highest exposure level at which no harmful effects were seen in the organ system studied. Key number 18 reports a NOAEL of 3 ppm for the respiratory system which was used to derive an intermediate exposure, inhalation MRL of 0.005 ppm (see footnote "c"). LOAEL A Lowest-Observed-Adverse-Effect Level (LOAEL) is the lowest exposure level used in the study that caused a harmful health effect. LOAELs have been classified into "Less Serious" and "Serious" effects. These distinctions help readers identify the levels of exposure at which adverse health effects first appear and the gradation of effects with increasing dose. A brief description of the specific end point used to A-3 APPENDIX A quantify the adverse effect accompanies the LOAEL. The "Less Serious" respiratory effect reported in key number 18 (hyperplasia) occurred at a LOAEL of 10 ppm. (10). Reference The complete reference citation is given in Chapter 8 of the profile. (11). CEL A Cancer Effect Level (CEL) is the lowest exposure level associated with the onset of carcinogenesis in experimental or epidemiological studies. CELs are always considered serious effects. The LSE tables and figures do not contain NOAELs for cancer, but the text may report doses which did not cause a measurable increase in cancer. (12). Footnotes Explanations of abbreviations or reference notes for data in the LSE tables are found in the footnotes. Footnote "c" indicates the NOAEL of 3 ppm in key number 18 was used to derive an MRL of 0.005 ppm. LEGEND See LSE Figure 2-1 LSE figures graphically illustrate the data presented in the corresponding LSE tables. Figures help the reader quickly compare health effects according to exposure levels for particular exposure duration. (13). Exposure Duration The same exposure periods appear as in the LSE table. In this example, health effects observed within the intermediate and chronic exposure periods are illustrated. (14). Health Effect These are the categories of health effects for which reliable quantitative data exist. The same health effects appear in the LSE table. (15). Levels of Exposure Exposure levels for each health effect in the LSE tables are graphically displayed in the LSE figures. Exposure levels are reported on the log scale "y" axis. Inhalation exposure is reported in mg,/m3 or ppm and oral exposure is reported in mg/kg/day. (16). NOAEL In this example, 18r NOAEL is the critical end point for which an intermediate inhalation exposure MRL is based. As you can see from the LSE figure key, the open-circle symbol indicates a NOAEL for the test species (rat). The key number 18 corresponds to the entry in the LSE table. The dashed descending arrow indicates the extrapolation from the exposure level of 3 ppm (see entry 18 in the Table) to the MRL of 0.005 ppm (see footnote "b" in the LSE table). (17). CEL Key number 38r is one of three studies for which Cancer Effect Levels (CELs) were derived. The diamond symbol refers to a CEL for the test species (rat). The number 38 corresponds to the entry in the LSE table. (18). (19). A-4 APPENDIX A Estimated Upper-Bound Human Cancer Risk Levels This is the range associated with the upper-bound for lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. These risk levels are derived from EPA’s Human Health Assessment Group's upper-bound estimates of the slope of the cancer dose response curve at low dose levels (q,"). Key to LSE Figure The Key explains the abbreviations and symbols used in the figure. [1] > TABLE 2-1. Levels oe ©0009 000000000000 04% %°% e » * . of Significant Exposure to [Chemical x] - Inhalation Exposure LOAEL (effect) Key to frequency/ NOAEL Less serious Serious figure? Species duration System (ppm) (ppm) (ppm) Reference [2]—> intermEDIATE EXPOSURE 7 [«}— 18 Rat 13 wk Resp 3 10 (hyperplasia) Nitschke et al. 1981 5d/wk 6hr/d CHRONIC EXPOSURE Cancer 38 Rat 18 mo 5d/wk 7hr/d 39 Rat 89-104 wk 5d/wk 6hr/d 40 Mouse 79-103 wk 5d/wk 6hr/d 20 (CEL, multiple Wong et al. 1982 V XIAN3ddV organs) 10 (CEL, lung tumors, NTP 1982 nasal tumors) 10 (CEL, lung tumors, NTP 1982 hemangiosarcomas) 2 The number corresponds to entries in Figure 2-1. [12}— B Used to derive an intermediate inhalation Minimal Risk Level (MRL) of 5 x 1073 ppm; dose adjusted for intermittent exposure and divided by an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability). CEL = cancer effect level; d = day(s); hr = hour(s); LOAEL observed-adverse-effect level; Resp = respiratory; wk = week(s) = lowest-observed-adverse-effect level; mo = month(s); NOAEL = no- S-V [1] —— + INTERMEDIATE CHRONIC (15-364 Days) (2365 Days) @- SLs WIN. ¢ LS 1.000 § 0 1@w Oh gy, Gum Ow Quy GeO on One Bse Bsa Bree Boe im wl 0 pw 0 x= 02 Oe gs On QO Ome Ow On Gu $ 16] — iY — ————— Qe On SOR H i V XIAN3ddV 9-V 001 § 000! § X ” 10e- LL © 10461 tor soins effects jardmahs) : oo001 mn Mose OD 10AEL tor leas sarienn oltocn (arbmats) MTT 10-7 * Rata O woAEL (erimeon 3 ofleck ether han concer 00000 L § Ouneapy @ cel Concm Eeci Level — A Markey The number nest lo each paint cor sspands to entries in Table 2 1 * Doses represent fo lowes! 600 lasted por $hudy hat reduced 6 emerdgenic respense and eo nut imply the ssistence of 8 Sveshald fer The cancer end paint FIGURE 2-1. Levels of Significant Exposure to [Chemical X]-Inhalation A-7 APPENDIX A Chapter 2 (Section 2.4) Relevance to Public Health The Relevance to Public Health section provides a health effects summary based on evaluations of existing toxicological, epidemiological, and toxicokinetic information. This summary is designed to present interpretive, weight-of-evidence discussions for human health end points by addressing the following questions. 1. What effects are known to occur in humans? 2. What effects observed in animals are likely to be of concern to humans? 3. What exposure conditions are likely to be of concern to humans, especially around hazardous waste sites? The section discusses health effects by end point. Human data are presented first, then animal data. Both are organized by route of exposure (inhalation, oral, and dermal) and by duration (acute, intermediate, and chronic). In vitro data and data from parenteral routes (intramuscular, intravenous, subcutaneous, etc.) are also considered in this section. If data are located in the scientific literature, a table of genotoxicity information is included. The carcinogenic potential of the profiled substance is qualitatively evaluated, when appropriate, using existing toxicokinetic, genotoxic, and carcinogenic daca. ATSDR does not currently assess cancer potency or perform cancer risk assessments. MRLs for noncancer end points if derived, and the end points from which they were derived are indicated and discussed in the appropriate section(s). Limitations to existing scientific literature that prevent a satisfactory evaluation of the relevance to public health are identified in the Identification of Data Needs section. Interpretation of Minimal Risk Levels Where sufficient toxicologic information was available, MRLs were derived. MRLs are specific for route (inhalation or oral) and duration (acute, intermediate, or chronic) of exposure. Ideally, MRLs can be derived from all six exposure scenarios (e.g., Inhalation - acute, -intermediate, -chronic; Oral - acute, - intermediate, - chronic). These MRLs are not meant to support regulatory action, but to aquaint health professionals with exposure levels at which adverse health effects are not expected to occur in humans. They should help physicians and public health officials determine the safety of a community living near a substance emission, given the concentration of a contaminant in air or the estimated daily dose received via food or water. MRLs are based largely on toxicological studies in animals and on reports of human occupational exposure. A-8 APPENDIX A MRL users should be familiar with the toxicological information on which the number is based. Section 2.4, "Relevance to Public Health," contains basic information known about the substance. Other sections such as 2.6, "Interactions with Other Chemicals" and 2.7, "Populations that are Unusually Susceptible" provide important supplemental information. MRL users should also understand the MRL derivation methodology. MRLs are derived using a modified version of the risk assessment methodology used by the Environmental Protection Agency (EPA) (Barnes and Dourson, 1988; EPA 1989a) to derive reference doses (RfDs) for lifetime exposure. To derive an MRL, ATSDR generally selects the end point which, in its best judgement, represents the most sensitive human health effect for a given exposure route and duration. ATSDR cannot make this judgement or derive an MRL unless information (quantitative or qualitative) is available for all potential effects (e.g., systemic, neurological, and developmental). In order to compare NOAELs and LOAELs for specific end points, all inhalation exposure levels are adjusted for 24hr exposures and all intermittent exposures for inhalation and oral routes of intermediate and chronic duration are adjusted for continous exposure (i.e., 7 days/week). If the information and reliable quantitative data on the chosen end point are available, ATSDR derives an MRL using the most sensitive species (when information from multiple species is available) with the highest NOAEL that does not exceed any adverse effect levels. The NOAEL is the most suitable end point for deriving an MRL. When a NOAEL is not available, a Less Serious LOAEL can be used to derive an MRL, and an uncertainty factor (UF) of 10 is employed. MRLs are not derived from Serious LOAELs. Additional uncertainty factors of 10 each are used for human variability to protect sensitive subpopulations (people who are most susceptible to the health effects caused by the substance) and for interspecies variability (extrapolation from animals to humans). In deriving an MRL, these individual uncertainty factors are multiplied together. The product is then divided into the adjusted inhalation concentration or oral dosage selected from the study. Uncertainty factors used in developing a substance-specific MRL are provided in the footnotes of the LSE Tables. ACGIH ADME ATSDR BCF BSC CDC CEL CERCLA CFR CLP cm CNS DHEW DHHS DOL ECG EEG EPA EKG FAO FEMA FIFRA HPLC hr IDLH IARC ILO in Kd Koc Kow LC LC, LCs LD, LDs, LOAEL LSE B-1 APPENDIX B ACRONYMS, ABBREVIATIONS, AND SYMBOLS American Conference of Governmental Industrial Hygienists Absorption, Distribution, Metabolism, and Excretion Agency for Toxic Substances and Disease Registry bioconcentration factor Board of Scientific Counselors Centers for Disease Control Cancer Effect Level Comprehensive Environmental Response, Compensation, and Liability Act Code of Federal Regulations Contract Laboratory Program centimeter central nervous system Department of Health, Education, and Welfare Department of Health and Human Services Department of Labor electrocardiogram electroencephalogram Environmental Protection Agency see ECG Food and Agricultural Organization of the United Nations Federal Emergency Management Agency Federal Insecticide, Fungicide, and Rodenticide Act first generation feet per minute foot Federal Register gram gas chromatography high performance liquid chromatography hour Immediately Dangerous to Life and Health International Agency for Research on Cancer International Labor Organization inch adsorption ratio kilogram octanol-soil partition coefficient octanol-water partition coefficient liter liquid chromatography lethal concentration low lethal concentration 50 percent kill lethal dose low lethal dose 50 percent kill lowest-observed-adverse-effect level Levels of Significant Exposure meter mg min mL mm mmo 1 mppcf MRL MS NIEHS NIOSH NIOSHTIC nm ng NHANES nmol NOAEL NOES NOHS NPL NRC NTIS NTP OSHA PEL Pg pmol PHS PMR ppb ppm PPC REL RfD RTECS sec SCE SIC SMR STEL STORET TLV TSCA TRI TWA U.S. UF WHO Iv Vv B-2 APPENDIX B milligram minute milliliter millimeters millimole millions of particles per cubic foot Minimal Risk Level mass spectroscopy National Institute of Environmental Health Sciences National Institute for Occupational Safety and Health NIOSH's Computerized Information Retrieval System nanometer nanogram National Health and Nutrition Examination Survey nanomole no-observed-adverse-effect level National Occupational Exposure Survey National Occupational Hazard Survey National Priorities List National Research Council National Technical Information Service National Toxicology Program Occupational Safety and Health Administration permissible exposure limit picogram picomole Public Health Service proportional mortality ratio parts per billion parts per million parts per trillion recommended exposure limit Reference Dose Registry of Toxic Effects of Chemical Substances second sister chromatid exchange Standard Industrial Classification standard mortality ratio short-term exposure limit STORAGE and RETRIEVAL threshold limit value Toxic Substances Control Act Toxic Release Inventory time-weighted average United States uncertainty factor World Health Organization greater than greater than or equal to TERXOSO®™R RIAA m x QQ equal to less than less than or equal to percent alpha beta delta gamma micron microgram B-3 APPENDIX B Cc-1 APPENDIX C PEER REVIEW A peer review panel was assembled for manganese. The panel consisted of the following members: Dr. Bernard Weiss, Professor of Toxicology, Environmental Health Science Center, University of Rochester, Rochester, New York; Dr. Paul Mushak, Private Consultant, Durham, North Carolina; Dr. Gerald Gianutsos, Associate Professor of Pharmacology, University of Connecticut, Storrs, Connecticut; Dr. Rolf Hartung, Professor of Environmental Toxicology, University of Michigan, Ann Arbor, MI; Dr. James Withey, Research Scientist, Environmental Health Center, Ottawa, Ontario, Canada. These experts collectively have knowledge of manganese’s physical and chemical properties, toxicokinetics, key health end points, mechanisms of action, human and animal exposure, and quantification of risk to humans. A second panel of reviewers was assembled to review the sections on mitigation of effects. This panel consisted of: Dr. Brent Burton, Medical Director, Oregon Poison Center, Oregon Health Sciences University, Portland, Oregon; Dr. Alan Hall, Private Consultant, Evergreen, Colorado; and Dr. Alan Woolf, Director of Clinical Pharmacology and Toxicology, Massachusetts Poison Control System, The Children’s Hospital, Boston, Massachusetts. All reviewers were selected in conformity with the conditions for peer review specified in the Comprehensive Environmental Response, Compensation, and Liability Act of 1986, Section 104. Scientists from the Agency for Toxic Substances and Disease Registry (ATSDR) have reviewed the peer reviewers’ comments and determined which comments will be included in the profile. A listing of the peer reviewers’ comments not incorporated in the profile, with a brief explanation of the rationale for their exclusion, exists as part of the administrative record for this compound. A list of databases reviewed and a list of unpublished documents cited are also included in the administrative record. The citation of the peer review panel should not be understood to imply its approval of the profile’s final content. The responsibility for the content of this profile lies with the ATSDR. ‘U.S. Government Printing Office: 1992 — 636-281 UC. BERKELEY LIBRARIES HAAR (03577305