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Reference Dose for Chronic Oral Exposure( RfD ) 

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0373
Manganese; CASRN 7439-96-5

Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data, as outlined in the IRIS assessment development process. Sections I (Health Hazard Assessments for Noncarcinogenic Effects) and II (Carcinogenicity Assessment for Lifetime Exposure) present the conclusions that were reached during the assessment development process. Supp orting information and explanations of the methods used to derive the values given in IRISare provided in the guidance documents located on the IRIS website.
STATUS OF DATA FOR Manganese

File First On-Line 09/26/1988

Oral RfD Assessment (I.A.) on-line 05/01/1996
Inhalation RfC Assessme nt (I.B.) on-line 12/01/1993 Carcinogenicity Assessm ent (II.) on-line 12/01/1996



### _I. Chronic Health Hazard Assess ments for Noncarcinogenic Effects

_I.A. Reference Dose for Chronic Oral Exposure (RfD)
Substance Name — Manganese CASRN — 7439-96-5 Last Revised — 05/01/1996
The oral Reference Dose (RfD) is based on the a ssumption that thresholdsexist for certain toxic effects such as cellular necrosis. It is expressed in units of mg/kg-day. In general, the RfD is an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk 

## Integrated Risk Information System http://www.epa.gov/iris/subst/0373.htm Last updated on Thursday, August 09, 2012 

### http://www.epa.gov/iris/subst/0373.htmCritical Effect Experimental Doses* of deleterious effects during a lifetime. Plea se refer to the Background Document for an elaboration of these concepts. RfDs can also be derived for the noncarcino genic health effects of substances that are also carcinogens. Therefore, it is essential to refer to other sources of information concerning the carcinogenicity of this substance. If the U.S. EPA has evaluated this substance for potential human carcinogenicity, a summary of that evaluation will be contained in Section II of this file.

NOTE: This reference dose is for the total oral in take of manganese. As discussed in the Principal and Supporting Studies and Uncertainty and Modifying Factors Sections, it is recommended that a modifying factor of 3 be applied if this RfD is used for assessments involving nondietary exposures.
__I.A.1. Oral RfD Summary
UF MF RfD

CNS effects

Human Chronic Ingestion Data
NRC, 1989; FreelandGraves et al., 1987; WHO, 1973; NOAEL (food): 0.14 mg/kg-day

LOAEL: None 1 1 1.4E-1 mg/kg-day

*Conversion Factors and Assumptions — The NOAEL of 10 mg/day (0.14 mg/kg-day for 70 kg adult) for chronic human consumption of manganese in the diet is based on a composite of data from several studies.
__I.A.2. Principal and Supporting Studies (Oral RfD)
Freeland-Graves, J.H., C.W. Bales and F. Behma rdi. 1987. Manganese requirements of humans. In: Nutritional Bioavailability of Manganese, C. Kies, ed. American Chemical Society, Washington, DC. p. 90-104.
NRC (National Research Council). 1989. Recomme nded Dietary Allowanc es, 10th ed. Food and Nutrition Board, National Rese arch Council, National Academ y Press, Washington, DC. p. 230- 235.
WHO (World Health Organization). 1973. Trace El ements in Human Nutritio n: Manganese. Report of a WHO Expert Committee. Tech nical Report Service, 532, WH O, Geneva, Switzerland. p. 34- 36.
Manganese is a ubiquitous elemen t that is essential for normal physiologic functioning in all animal species. Several di sease states in humans have been a ssociated with both deficiencies and excess intakes of manganese. Th us any quantitative risk asse ssment for manganese must take into account aspects of both the essentiality an d the toxicity of manganese. In humans, many data are available providing information about the range of essentiality for manganese. In addition, there are many report s of toxicity to humans expose d to manganese by inhalation; much less is known, however, about oral inta kes resulting in toxici ty. As discussed in the Additional Studies / Comments Section, rodents do not provide a good experimental model for manganese toxicity, and only one limited study in primates by the oral route of exposure is 

### http://www.epa.gov/iris/subst/0373.htmavailable. The following assessment, therefore, focu ses more on what is known to be a safe oral intake of manganese for the general human populati on. Finally, it is important to emphasize that individual requirements for, as well as adverse reacti ons to, manganese may be highly variable. The reference dose is estimated tobe an intake for the general po pulation that is not associated with adverse health effects; this is not meant toimply that intakes above the reference dose are necessarily associated with toxicity. Some in dividuals may, in fact, consume a diet that contributes more than 10 mg Mn/daywithout any cause for concern.

The Food and Nutrition Board of the National Research Coun cil (NRC, 1989) determined an "estimated safe and adequate daily dietary intake " (ESADDI) of manganese to be 2-5 mg/day for adults. The lower end of this range was based on a study by McLeod and Robinson (1972), who reported equilibrium or positive balances at intakes of 2.5 mg Mn/day or higher. The range of the ESADDI also includes an "extra margin of sa fety" from the level of 10 mg/day, which the NRC considered to be safe for an occasional intake.

While the NRC determined an ESAD DI for manganese of 2-5 mg/day, some nutritionists feel that this level may be too low. Freeland-Graves et al . (1987) have suggested a range of 3.5-7 mg/day for adults based on a review of human studies. Itis noted that dietary habits have evolved in recent years to include a larger proportion of me ats and refined foods in conjunction with a lower intake of whole grains. The net result of such dietary changes includes a lower intake of manganese such that many individuals may have suboptimal manganese status. This is discussed in more detail in the Additional Studies / Comments Section.
The World Health Organization (WHO, 1973) review ed several investigatio ns of adult diets and reported the average daily consumption of mangan ese to range from 2.0- 8.8 mg Mn/day. Higher manganese intakes are a ssociated with diets high in whol e-grain cereals, nuts, green leafy vegetables, and tea. From mang anese balance studies, the WHO concluded that 2-3 mg/day is adequate for adults and 8-9 mg /day is "perfectly safe."

Evaluations of standard diets from the United States, England, and Holland reveal average daily intakes of 2.3-8.8 mg Mn/day. Depending on indivi dual diets, however, a normal intake may be well over 10 mg Mn/day, especially from a vegetari an diet. While the actual intake is higher, the bioavailability of manganese from a vegetarian diet is lower, thereby decreasing the actual absorbed dose. This is discussed in more detail in the Additional Stud ies / Comments Section.
From this information taken together, EPA conc ludes that an appropriate reference dose for manganese is 10 mg/day (0.14 mg/kg-day). In a pplying the reference dose for manganese to a risk assessment, it is important that the assessor consider the ubiquitous nature of manganese, specifically that most individuals will be consuming about 2-5 mg Mn/day in their diet. This is particularly important when one is using th e reference dose to determine acceptable concentrations of manganese in water and soils.
There is one epidemiologic study of manganese in drinking water, performed by Kondakis et al. (1989). Three areas in northwest Greece werechosen for this study, with manganese concentrations in natural well wa ter of 3.6-14.6 ug/L in area A, 81.6-252.6 ug/L in area B, and 1600-2300 ug/L in area C. The total population of the three areas studied ranged from 3200 to 4350 people. The study included onlyindividuals over the age of 50drawn from a random sample of 10% of all households (n= 62, 49 and 77 for areas A, B and C, respectively). The authors reported that "all areas were similar with respect to social and dietary characteristics," but few details were reported. The three areas are locate d within a 200-square km region. Although the amount of manganese in the diet was not reported , the authors indicated th at most of the food was purchased from markets and is expected to be comparable for all three areas. Chemicals 

### http://www.epa.gov/iris/subst/0373.htmother than manganese in the well water were re ported to be within Economic Community (EC) standards, except for hardness (120-130 mg calciu m carbonate per liter). The individuals chosen were submitted to a neurologic examination, th e score of which represents a composite of the presence and severity of 33 symptoms (e.g., weakness/fatigue, gait disturbances, tremors, dystonia). Whole blood and hair manganese conc entrations also were determined. The mean concentration of manganese in hair was 3.51, 4. 49 and 10.99 ug/g dry weight for areas A, B and C, respectively (p<0.0001 for area C versus A). The concentration of manganese in whole blood did not differ between the three areas, but this is not considered to be a reliable indicator of manganese exposure. The mean (x) and range (r) of neurologic scores were as follows: Area A (males: x=2.4, r=0-21; females: x=3.0, r=0-18; both x=2.7, r=0-21); Area B (males x=1.6, r=0-6; females: x=5.7 r=0-43; both: x=3.9, r=0-43); and Area C (males: x=4.9, r=0-29; females: x=5.5, r=0-21; both x=5.2, r=0-29). Th e authors indicate that the difference in mean scores for area C versus A was significantly increased (Mann-Wh itney z=3.16, p= 0.002 for both sexes combined). In a subsequent analysis, logisticregression indicated that there is a significant difference between areas A and C even when both age and sex are taken in to account (Kondakis, 1990).
The individuals examined in the Kondakis study also had exposure to ma nganese in their diet. This was originally estimated to be 10-15 mg/daybecause of the high intake of vegetables (Kondakis, 1990). This estimatewas subsequently lowered to 5-6 mg/day (Kondakis, 1993). Because of the uncertainty in the amount of manganese in the diet and the amount of water consumed, it is impossible to estimate the total oral intake of manganese in this study. These limitations preclude the use of this study to de termine a quantitative dose-response relationship for the toxicity of manganese in humans.
This study, nevertheless, raises significant concerns about possible adverse neurological effects at doses not far from the range of e ssentially. Because of this concern, it is recommended that a modifying factor of 3 be applied when assessing risk from manganese in drinking water or soil. This is discussed more ful ly in the Uncertainty and Modifying Factors Section.

__I.A.3. Uncertainty and Mo difying Factors (Oral RfD)

UF — The information used to determine the RfD for manganese was taken from many large populations consuming normal diets over an exte nded period of time with no adverse health effects. As long as physiologic systems are not overwhelmed, humans exert an efficient homeostatic control over manganes e such that body burdens are ke pt constant with variation in the manganese content of the diet. The informat ion providing a chronic NOAEL in many crosssections of human populations, ta ken in conjunction with the essent iality of manganese, warrants an uncertainty factor of 1.
MF — When assessing exposure to manganese from food, the modifying factor is 1; however, when assessing exposure to manganese from drin king water or soil, a modifying factor of 3 is recommended. As discussed more fu lly in the Additional Studies/Comments Section, there are four reasons for this recommendation. First, while the data suggest that there is no significant difference between absorption of ma nganese as a function of the form in which it is ingested (i.e., food versus water), there is some degree of increased uptake of manganese from water in fasted individuals. Second, the study by Kondakis et al . (1989) raises some conc ern for possible adverse health effects associated with a lifetime consumption of drinking water containing about 2 mg/L of manganese. Third, although toxicity has not been demonstrated, there is concern for infants fed formula that typically has a much higher concentration of manganese than does human milk. If powdered formula is made with drinking water, the manganese in the water would represent an additional source of intake. Finally, there issome evidence that neonates absorb more 

### http://www.epa.gov/iris/subst/0373.htmmanganese from the gastrointestin al tract, that neonates are le ss able to excrete absorbed manganese, and that in the neon ate the absorbed manganese moreeasily passes the blood-brain barrier. These findings may be related to the fact that manganese in formula is in a different ionic form and a different physical state than in human milk. These considerations concerning increased exposure in an import ant population group, in addition to the likelihood that any adverse neurological effects of manganese are likely to be irreversible and not manifested for many years after exposure, warrant caution until more definitive data are available.

__I.A.4. Additional Stud ies/Comments (Oral RfD)
The biochemical role of manganese is to serve as an activator of several enzymes including hydrolases, kinases, decarboxylases and transferases. It is also required fo r the activity of three metalloenzymes: arginase, pyruvate carboxylas e and mitochondrial superoxide dismutase. A review of the biochemical and nutri tional roles of manganese in huma n health, as well as a list of disease states related to manganese deficiencyor excess, is provided by Wedler (1994).
Because of the ubiquitous nature of manganese in foodstuffs, actual manganese deficiency has not been observed in the general population. There are, however, only two reports in the literature of experimentally induced manganese deficiency in humans. The first was a report by Doisy (1972), who inadvertently om itted manganese from a formulat ed diet. One of two subjects developed a slight reddening of the hair, a scaly tran sient dermatitis, marked hypocholesterolemia, and modera te weight loss. The diet was subsequently determined to contribute 0.34 mg Mn/day, a level that resulted in manganese deficiency. The second report was a metabolic balance study conducted by Friedman et al. (1987) in which seven male volunteers were fed a semipurified diet containing 0.11 mg Mn/day for 39 days. Transient dermatitis developed in five of the seven su bjects by the 35th day, which th e authors speculate was a result of decreased activity of glycosyltransferases or prolidase, manganese- re quiring enzymes that are necessary for dermal maintenance. Hypocholesterolemia was also ob served in this study, which the authors suggest was a result of the need fo r manganese at several st eps in the cholesterol biosynthesis pathway.
While an outright manganese deficiency has not been observed in the general human population, suboptimal manganese status may be more of a concern. As reviewed by Freeland-Graves and Llanes (1994), several disease states have been associated with low leve ls of serum manganese. These include epilepsy, exocrine pancreatic insufficiency, multiple sclerosis, cataracts, and osteoporosis. In addition, several inborn errors of metabolism ha ve been associated with poor manganese status (e.g., phenylketonuria, maple syrup urine disease). While a correlation has been shown for low levels of serum manganese an d these disease states, a causal relationship has not been demonstrated, and th is remains an area in which a dditional research is needed.
To better understand the consequences of mang anese deficiency, several animal models have been studied. These have al so been reviewed by Freeland-Graves and Llanes (1994). Experiments in several species have shown a deficiency in di etary manganese to result in disorders in lipid and carbohydrate metabolism, impaired growth and reproductive function, and ataxia and skeletal abno rmalities in neonates.
While manganese is clearly an es sential element, it has also been demonstrated to be the causative agent in a syndrome of neurologic and psychiatric disorders that has been described in manganese miners. Donaldson (1987) provides a summary of this docu mented toxicity of manganese to humans, which has been primarily limited to workers exposed by inhalation. In contrast to inhaled manganese, ingested manganese has rarely b een associated with toxicity. A 

### http://www.epa.gov/iris/subst/0373.htmreview of manganese toxicity in humans and expe rimental animals has been provided by Keen and Zidenberg-Cherr (1994).
A report by Kawamura et al. (1941) is the on ly epidemiologic study describing toxicologic responses in humans co nsuming large amounts of manganese dissolved in drinking water. The manganese came from ab out 400 dry- cell batteries buried near a drinking water well, resulting in high levels of both manganese and zinc in the water. Twenty-five cases of manganese poisoning were reported, with symptoms includin g lethargy, increased muscle tonus, tremor and mental disturbances. The most se vere symptoms were observed in elderly people, while children appeared to be unaffected. Thre e individuals died, one from suic ide. The cause of death for the other two was not reported, but the autopsy of one individual revealed manganese concentration in the liver to be 2-3 times higher than in control autopsies. Zinc levels also were increased in the liver. The well water was not analyzed until 1 month after the outbreak, at which time it was found to contain approximately 14 mg Mn/L. When re-analyzed 1 month later, however, the levels were decreased by about ha lf. Therefore, by retrospective extrapolation, the concentration of manganese at the time of exposure may havebeen as high as 28 mg Mn/L. No information regarding dietary levels of manganese was available in this study.
A few case studies have also pointed to the po tential for manganese poisoning by routes other than inhalation. One involved a 59-year-old male who was admitted to the hospital with symptoms of classical manganese poisonin g, including dementia and a generalized extrapyramidal syndrome (Banta and Markesbery, 1977). The patien t's serum, hair, urine, feces and brain were found to have manganese "elevated beyond toxic levels," perhaps a result of his consumption of "large doses of vitamins and minerals for 4 to 5 years." Unfortunately, no quantitative data were reported.
Another case study of manganese intoxication involved a 62-year-old male who had been receiving total parenteral nutrition that provided 2.2 mg of manganese (form not stated) daily for 23 months (Ejima et al ., 1992). The patient's whole blood ma nganese was found to be elevated, and he was diagnosed as having parkinsonism, wi th dysarthria, mild rigidity, hypokinesia with masked face, a halting gait and severely impaired postural reflex es. To be able to compare the manganese load in this individual with that corresponding to an oral intake, the difference between the direct intravenous exposure and the re latively low level of absorption of manganese from the GI tract must be taken into account. Assuming an average absorp tion of roughly 5% of an oral dose, the intravenous dose of 2.2 mg Mn /day would be approximately equivalent to an oral intake of 40 mg Mn/day.
A third case study involved an 8-year old girl wi th Alagille's syndrome (an autosomal dominant disorder manifested prin cipally by neonatal chol estasis and intrahepatic bile duct paucity) and end-stage liver disease (Devenyi et al., 1994). Th e patient had a stable peripheral neuropathy and for 2 months manifested with episodic, dystonic posturing and cramping of her hands and arms. Whole blood manganese was elevated (27 ug/L; normal range: 4-14 ug/L) and cranial T1- weighted magnetic resonance imaging (MRI) reveal ed symmetric hyperintense globus pallidi and subthalamic nuclei. These were taken as indicati ons of manganese neurotoxicity. Following liver transplantation, the patient's manganese levelsreturned to normal, neurological symptoms improved and MRI appeared normal. It appeared, then, that the progression of liver dysfunction had resulted in inadequate excretion of mang anese into the bile, ultimately leading to neurotoxicity. With restoration of liver function, this was remedied . This case study suggests that for individuals with impaired liver function, inta kes of manganese that would otherwise be safe may present a problem. 

### http://www.epa.gov/iris/subst/0373.htmAlthough conclusive evidence is lacking, some in vestigators have also linked increased intakes of manganese with violent be havior. Gottschalk et al. (1991) found statistically sign ificant elevated levels of manganese in the hair of convicted felons (1.62 +/- 0.173 ppm in prisoners compared with 0.35 +/- 0.020 ppm in controls). The authors su ggest that "a combinatio n of cofactors, such as the abuse of alcohol or other chemical substanc es, as well as psychosocial factors, acting in concert with mild manganese toxicity may prom ote violent behavior." Caution should be exercised to prevent reading too much into these da ta, but support for this hypothesis is provided by studies of a population of Ab origines in Groote Eylandt. Several clinical symptoms consistent with manganese intoxication are present in about 1% of the inhabitants of this Australian island, and it may not be coincidental that the proportion of arrests in this native population is the highest in Australia (Cawte and Fl orence, 1989; Kilburn, 1987). The soil in this region is very high in manganese (40,000-50,000 ppm), and the fruits an d vegetables grown in the region also are reported to be high in manganes e. Quantitative data on oral intakes have not been reported, but elevated concentrations of manganese have be en determined in the blood and hair of the Aborigines (Stauber et al., 1987). In addition to the high levels of envi ronmental ma nganese, other factors common to this po pulation may further increase the propensity for manganism: high alcohol intake, anemia, and a diet deficient in zinc and several vitamins (Florence and Stauber, 1989).
Only one limited oral study has been performed in a group of four Rhesus monkeys (Gupta et al., 1980). Muscular weakness and rigidity of the lowe r limbs developed after 18 months of exposure to 6.9 mg Mn/kg-day (as MnC12.4H 2O). Histologic analysis show ed degenerated neurons in the substantia nigra and scanty neuromelanin granulesin some other pigmented cells. While it is clear that neurotoxicity resultin g from excessive exposure to ma nganese is of primary concern, the exact mechanism is not clear. Histopathologically, the globus pallidus and substantia nigra appear to be most affect ed. Biochemically, deficiencies of striatal do pamine and norepinephrine appear to be fundamental. As reviewed by Aschner and Aschner (1991), multiple pathways that contribute to manganese-induced neurotoxicity are likely.

Several oral studies have been performed in rodents, also demo nstrating biochemical changes in the brain following administrati on of 1 mg MnC12.4H2O/mL in drinking water (approximately 38.9 mg Mn/kg-day) (Chandra and Shukla, 1981; Lai et al., 1981, 1982; Leung et al., 1981). However, rodents do not exhibit the same neurolog ic deficits that humans do following exposure to manganese; thus the relevance of these biochemical changes has been challenged. The problem with using rodents is exemplified by the disease of parkinsonism, which is characterized by effects very similar to th ose seen in manganese poisonin g. Marsden and Jenner (1987) hypothesize that the ability of certain drugs to in duce parkinsonism in primates but not in rodents is due to the relative lack of neuromelanin in rodents. Because manganese selectively accumulates in pigmented regions of the brain (e.g., the substantia nigra), this species difference is fundamentally important.
EPA initiated an investigation of the literature to determine the relative bioavailability of manganese in food and water (Ruoff, 1995). The co nclusions from this research were that under a wide variety of exposure scenarios in humans , the bioavailability of manganese ingested in water was essentially equal to the bioavailability of manganese in food. Total diet, rather than the actual medium of exposure, appe ars to be more of a determin ing factor for the uptake of manganese from the GI tract. Specifically, the re lative bioavailability of manganese from food compared with that from drinking water was determined to be 0.7, and not statistically significantly different. When the da ta were reanalyzed toinclude only the ingestion of manganese in drinking water by fasted individuals, the rela tive bioavailability was 0.5, indicating roughly a 2-fold greater uptake of manganese from drin king water compared with uptake from food. 

### http://www.epa.gov/iris/subst/0373.htmAnother issue of great importance to consider in the risk assessment for manganese concerns the bioavailability of different forms of manganese consumed under different exposure conditions. Various dietary factors as well as the form of manganese can have a significant bearing on the dose absorbed from the GI tract. Many constituen ts of a vegetarian diet (e.g., tannins, oxalates, phytates, fiber) have been fo und to inhibit manganese absorp tion presumably by forming insoluble complexes in the gut. In addition, high dietary levels of calcium or phosphorus have been reported to decrease manganese absorp tion. Individuals who are deficient in iron demonstrate an increase in manganese absorption. It is also recognized that manganese uptake and elimination are under homeostatic control, ge nerally allowing for a wide range of dietary intakes considered to be safe. These factors and others are described in a review by Kies (1987). In addition to the influence of extrinsic variab les, significant interindividual differences in manganese absorption and retention have been reported. In humans administered a dose of radiolabeled manganese in an infant formula, the mean absorption wa s 5.9 +/- 4.8%, but the range was 0.8-16%, a 20-fold difference (David sson et al., 1989). Retention at day 10 was 2.9 +/- 1.8%, but the range was 0.6-9.2%, again indicating substantial differences between individuals.
In a 100-day dietary study in 6-week-old male mice, Komura and Sakamoto (1991) demonstrated significant differen ces in tissue levels of manganese in mice fed equivalent amounts of manganese as MnCl 2.4H2O, Mn(Ac)2.4H2O, MnCO3 an d MnO2. Mice receiving the two soluble forms of manganese (the chloride and acetate salts) were found to gain significantly less weight than controls, while mice consuming the insoluble forms of manganese (the carbonate and dioxide salts) appeared to actually gain slightly more weightthan controls. The acetate and carbonate groups, however, had significantly higher manganese levels in the liver and kidney compared with the chloride and dioxide groups, bo th of which were elevated above control levels. Reduced locomotor activity in the carbonate and acetate groups was also reported, perhaps related to the higher tissue levels of manganese. This study points out a need for understanding the effects of the various chemical species of manganese, of which relatively little is known. More information on manganese speciation can be found in the RfC file on IRIS.
It is also recognized th at neonates may be at increased risk of toxicity resulting from exposure to manganese because of a higher level of uptake from the GI tract and a decreased ability to excrete absorbed manganese. The uptake and re tention of manganese ha ve been reviewed by Lonnerdal et al. (1987). In rats, manganese abso rption decreased dramat ically as the animals matured. While 24-hour retention values are as high as 80% in 14-day-old pups, this value drops to about 30% by day 18. Low levels of manganese absorption (about 3-4%) have also been reported for mature humans, but fe w data are available for infants.
No reports of actual manganese toxicity or defici ency have been reported for infants. As with adults, however, the potential for effects re sulting from excess mang anese or suboptimal manganese appears to e xist (reviewed by Lonnerdal, 1994). In particular, suboptimal manganese may be a problem for preterm infants given calciu m supplementation, which is known to inhibit the absorption of manganese. Be cause manganese is required for adequate bone mineralization, it is suggested that insufficient absorption of manganese in preterm infants may contribute to poor bone growth. On the othe r hand, excess manganese may be a problem for infants with low iron status, as this is known to increase the absorption of manganese.

An additional concern for infants has been ex pressed because of the often high levels of manganese in infant formulas, particularly compared with breast milk. Also, manganese in human milk is in the trivalent form bound to lactoferrin, the major iron-binding protein. Lactoferrin receptors are located in the brush border membrane s of epithelial cells throughout the length of the small intestine, thus allowing for regulation of the uptake of manganese. In infant formulas, 

### http://www.epa.gov/iris/subst/0373.htmhowever, because manganese is in the divalent st ate, absorption through the GI tract cannot be regulated by lactoferrin receptors. Collipp et al. (1983) found th at hair mangan ese levels in newborn infants increased significantly from birth (0.19 ug/g) to 6 weeks of age (0.865 ug/g) and 4 months of age (0.685 ug/g) when the infants weregiven formula, but thatthe increase was not significant in babies who were breast- fed (0.330 ug/g at 4 mont hs). While human breast milk is relatively low in manganese (7-15 ug/L), levelsin infant formulas are much higher (50-300 ug/L). It was further reported in this study that the level of manganese in the hair of learningdisabled children (0.434 ug/g) was significantly in creased in comparison with that of normal children (0.268 ug/g). Other investigators also have reported an associ ation between elevated levels of manganese in hair and learning disabili ties in children (Barlow and Kapel, 1979; Pihl and Parkes, 1977). Although no causal relationship has been determined for learning disabilities and manganese intake, further re search in this area is warranted. High levels of manganese in infant formulas may be of concern because of the increa sed absorption and retent ion of manganese that has been reported in neonatal animals (Lonnerdal et al., 1987). Also, manganese has been shown to cross the blood-brain barrier, with the rate of penetration in animal experiments being 4 times higher in neonates than in adults (Mena, 1974).

__I.A.5. Confidence in the Oral RfD
Study — Medium Database — Medium RfD — Medium
Many studies have reported similar findings wi th regard to the normal dietary intake of manganese by humans. These data are considered to be superior to any data obtained from animal toxicity studies, especially as the physiologic requirements for manganese vary quite a bit among different species, with man requiring less th an rodents. There is no single study used to derive the dietary RfD for mangan ese. While several studies have determined average levels of manganese in various diets, no quantitative information is available to indicate toxic levels of manganese in the diet of humans. Because of the homeostatic control humans maintain over manganese, it is generally not considered to be very toxic when ingested with the diet. It is important to recognize that whil e the RfD process involves the de termination of a point estimate of an oral intake, it is also stated that this estimate is asso ciated "with uncertainty spanning perhaps an order of magnitude." Numerous fact ors, both environmental factors (e.g., the presence or absence of many dietary constituents ) and biological or host factors (e.g., age, alcohol consumption, anemia, liver function, genera l nutritional status) can significantly influence an individual's manganese status. As discussed in the Additional Studies / Comments Section, there is significant variability in the absorption and elimination of manganese by humans. Confidence in the data base is medium and confidence in the dietary RfD for manganese is also medium.

__I.A.6. EPA Documentation and Review of the Oral RfD

Source Document — This assessment is not presented in any existing EPA documentation.
This summary has been peer reviewed by three external scientists and has also received internal EPA review. The review was co mpleted on 07/06/1995. The comme nts of the reviewers have been carefully evaluated and considered in the re vision and finalization of this IRIS Summary. A record of these comments is included in the IRIS documentation files.

Other EPA Documentat ion — U.S. EPA, 1984 

### http://www.epa.gov/iris/subst/0373.htmCritical Effect Exposures* Agency Work Group Review — 05/17/1990, 06/21/1990, 06/24/1992, 09/22/1992, 03/31/1993, 12/14/1993, 05/12/1995

Verification Date — 05/12/1995
Screening-Level Literature Review Findings — A screening-level review conducted by an EPA contractor of the more recent toxicology literat ure pertinent to the RfD for Manganese conducted in September 2002 did not identifyany critical new studies. IRISusers who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or (202) 566-1676.

__I.A.7. EPA Contacts (Oral RfD)
Please contact the IRIS Hotline for all questions co ncerning this assessment or IRIS, in general, at (202)566-1676 (phone), (202)566-1749 (FAX) or hotline.iris@epa.gov (internet address).

_I.B. Reference Concentration for Chronic Inhalation Exposure (RfC)
Substance Name — Manganese CASRN — 7439-96-5 Last Revised — 12/01/1993
The inhalation Reference Concentration (RfC) is an alogous to the oral RfD and is likewise based on the assumption that thresholds exist for cert ain toxic effects such as cellular necrosis. The inhalation RfC considers toxic effects for both the respiratory system (portal-of-entry) and for effects peripheral to the respirat ory system (extrarespiratory effect s). It is expre ssed in units of mg/cu.m. In general, the RfC is an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily inhalation exposure of the human population (including sensitive subgroups) that is likely to be without an apprecia ble risk of deleterious e ffects during a lifetime. Inhalation RfCs were derived ac cording to the Interim Methods for Development of Inhalation Reference Doses (EPA/600/8-88/066FAugust 1989) and su bsequently, according to Methods for Derivation of Inhalation Reference Concentrat ions and Application of Inhalation Dosimetry (EPA/600/8-90/066F October 1994). RfCs can also be derived for the noncarcinogenic health effects of substances that are carc inogens. Therefore, it is essential to refer to other sources of information concerning the carcinogenicity of this substance. If the U.S. EPA has evaluated this substance for potential human carcinogenicity, a summary of that evaluation will be contained in Section II of this file.

__I.B.1. Inhalation RfC Summary
UF MF RfC

Impairment of neurobehavioral function
Occupational exposure to manganese dioxide
Roels et al., 1992 NOAEL: None LOAEL: 0.15 mg/cu.m
LOAEL(ADJ): 0.05 mg/cu.m LOAEL(HEC): 0.05 mg/cu.m 1000 1 5E-5 mg/cu.m 

### http://www.epa.gov/iris/subst/0373.htmImpairment of neurobehavioral function
Occupational exposure to manganese oxides and salts
Roels et al., 1987 NOAEL: None LOAEL: 0.97 mg/cu.m
LOAEL(ADJ): 0.34 mg/cu.m LOAEL(HEC): 0.34 mg/cu.m

*Conversion Factors and Assumptions: Roels et al., 1992: The LOAEL is derived from an occupational-lifetime integrated respirable dust (IRD) concentration of manganese dioxide (MnO2)(based on 8-hour TWA occupational exposure multiplied by individual work histories in years) expressed as mg manganese (Mn)/cu.m x years. The IRD concentrations ranged from 0.040 to 4.433 mg Mn/cu.m x years, with a geometric mean of 0.793 mg Mn/cu.m x years and a geometric standard deviation of 2.907. The geometric mean concentration (0.793mg/cu.m x years) was divided by the average duration of MnO2 exposure (5.3 years) to obtain a LOAEL TWA of 0.15 mg/cu.m. The LOAEL refers to an extrarespiratory effect of particulate exposure and is based on an 8-hour TWA occupational exposure. MVho = 10 cu.m/day, MVh = 20 cu.m/day. LOAEL(HEC) = 0.15 mg/cu.m x (MVho/MVh)x 5 days/7 days = 0.05 mg/cu.m.
Roels et al., 1987: The LOAEL isbased on an 8-hour TWA occu pational exposure. The TWA of total airborne manganese dust ranged from 0. 07 to 8.61 mg/cu.m, and the median was 0.97 mg/cu.m. This is an extrarespiratory effect of a particulate exposure. MVho = 10 cu.m/day, MVh = 20 cu.m/day. LOAEL(HEC) = 0.97 mg/cu.m x (M Vho/MVh) x 5 days/7 days = 0.34 mg/cu.m.

__I.B.2. Principal and Supp orting Studies (Inhalation RfC)
Roels, H., R. Lauwerys, J.-P. Buchet et al. 1987. Epidemiological survey among workers exposed to manganese: Effects on lung, ce ntral nervous system, and some bi ological indices. Am. J. Ind. Med. 11: 307-327.
Roels, H.A., P. Ghyselen , J.P. Buchet, E. Ceulemans, and R. R. Lauwerys. 1992. Assessment of the permissible exposure level to ma nganese in workers exposed to manganese dioxide dust. Br. J. Ind. Med. 49: 25-34.
Roels et al. (1992) conducted a cross-sectional study of 92 maleworkers exposed to manganese dioxide (MnO2) dust in a Belgian alkaline battery plant. A cont rol group of 101 male workers was matched for age, height, weight, work schedule , coffee and alcohol cons umption, and smoking; educational level was slightly higher in the control group (p= 0.046 by chi square test).
The manganese (Mn)-exposed group had been ex posed to MnO2 for an average of 5.3 years (range: 0.2-17.7 years). The geom etric means of the workers' TWA airborne Mn concentrations, as determined by personal samp ler monitoring at the breathing zone, were 0.215 mg Mn/cu.m for respirable dust and 0.948 mg Mn/cu.m for total dust. No data on particlesize or purity were presented, but the median cut po int for the respirable dust fraction was 5 um according to information provided by Roel s et al. (1992) and Roels (1993) . Total and respirable dust concentrations were highly correlated (r = 0.90, p < 0.001), with th e Mn content of the respirable fraction representing on average 25% of the Mn content in the total dust. The authors noted that the personal monitoring data we re representative of the usual exposure of the workers because work practices had not changed during the la st 15 years of the operation of the plant. 

### http://www.epa.gov/iris/subst/0373.htmOccupational-lifetime integrated exposure to Mn was estimated for each worker by multiplying the current airborne Mn concentrat ion for the worker's job classifi cation by the number of years for which that classification was held and adding the resulting (arithmetic) products for each job position a worker had held. The geometric mean occupational-lifetime integrated respirable dust (IRD) concentration was 0.793 mg Mn/cu.m x ye ars (range: 0.040-4.433 mg Mn/cu.m x years), with a geometric standard deviation of 2.907 mg Mn/cu.m x years, based on information provided by Roels (1993). The geometric mean occu pational-lifetime integrated total dust (ITD) concentration was 3.505 mg Mn/cu.m x years (range: 0.191-27.465 mg Mn/cu.m x years). Geometric mean concentrations of blood Mn (MnB) (0.81 ug/dL) and urinary Mn (MnU) (0.84 ug/g creatinine) were significantly higher in the Mn-exposed group than in the control group, but on an individual basis no significant correlat ion was found between either MnB or MnU and various external exposure para meters. Current respirable and total Mn dust concentrations correlated significantly with geometric mean MnU on a group basis (Spearman r = 0.83, p < 0.05).
A self-administered questionnaire focused on occupational and medical history, neurological complaints, and respiratory symptoms. Lung function was evaluated by standard spirographic measures. Neurobehavioral function was evaluated by tests of audio-verb al short-term memory, visual simple reaction time, ha nd steadiness, and eye-hand c oordination. Blood samples were assayed for several hematological parameters (erythrocyte count, leukocyte count, hemoglobin, hematocrit, mean corpuscular volu me, mean corpuscular hemoglobin , platelets, and differential leukocyte count); Mn; lead; zinc protoporphyrin; and serum levels of calcium, iron, follicle stimulating hormone (FSH), luteinizing hormone (LH), and prolactin. Urinary Mn, cadmium, and mercury concentrations were also determined.
Responses to the questionnaire indicated no sign ificant differences betw een groups in either respiratory or neurological symptoms, nor were spirometric, hormonal, or calcium metabolism measurements significantly different for the two groups. In addition, a separate report (Gennart et al., 1992) indicated no signific ant difference in the fe rtility of 70 of these workers, in contrast to earlier findings in 85 workers exposed not only to MnO2 but also to other Mn oxides and salts at higher concentrations (Lauwe rys et al., 1985). Erythropoiet ic parameters and serum iron concentrations were consistently and significantly lower in the Mn-exposed workers, albeit within the normal range of values.
Of particular note, Mn workers performed wo rse than controls on several measures ofneurobehavioral function. Visual reaction time was consistently and significantly slower in the Mnexposed workers measured in four 2-minute periods, with morepronounced slowing over the total 8-minute period and significantly greater va riability in reaction ti mes for the Mn-exposed group. Abnormal values for mean reaction times (defined as greater than or equal to the 95th percentile of the contro l group) also were significantly moreprevalent in the Mn-exposed group during three of four 2-minute intervals of the 8-minute testing period.
Five measures of eye-hand coordination (precision, percent precision, imprecision, percent imprecision, and uncertainty) re flected more erratic control of fine hand-forearm movement in the Mn-exposed group than in the controls, with mean scores on all five measures being highly significantly different for the two groups. There was also a significantly greater prevalence of abnormal values for these five me asures in the Mn-exposed group. The hole tremormeter test of hand steadiness indicated a cons istently greater amount of trem or in the Mn-exposed workers, with performance for two of the five hole size s showing statistically significant impairment.
Roels et al. (1992) performed an exposure-response analysis by cl assifying IRD values into three groups (<0.6, 0.6-1.2, and >1.2 mg Mn/cu. m x years) and comparing the prevalence of 

### http://www.epa.gov/iris/subst/0373.htmabnormal scores for visual reacti on time, hand steadiness, and eye-hand coordination with controls. This analysis indicated that the preval ence of abnormal eye-ha nd coordination values was significantly greater in workers whose IRD levels were less than 0.6 mg Mn/cu.m x years. However, the relationship betw een exposure and response was not linear across groups. Visual reaction time and hand steadine ss showed linear exposure- rela ted trends but did not achieve statistical significance except at levels of >1.2 mg Mn/cu.m x years. As noted by the authors, "analysis of the data on a group basis ... does not permit us to identify a threshold effect level for airborne Mn." Although sugges tive of a LOAEL of <0.6 mg Mn/cu.m x years, the exposureresponse analysis by Roels et al. (1992) possiblycould reflect the small disparity in educational level between exposed and control workers that was noted above with regard to the matching criteria for this study. If educational level we re in fact a covariate of exposure as well as neurobehavioral performance, it could confound the exposure-response anal ysis. Although it is not clear that such was the case, the possibilityof confounding suggests that the LOAEL should not be based on the results of the exposure-response analysis until these results can be confirmed by other studies. Al so, statistical correction for mu ltiple comparisons should be included in the exposure response analysis.
A LOAEL may be derived from the Roels et al. (1992) study by using th e IRD concentration of MnO2, expressed as mg Mn/cu.m x years (based on 8-hour TWA occupational exposures for various job classifications, multiplied by individual work histories in years). Dividing the geometric mean IRD concentration (0.793 mg/cu.m x years) by the average duration of the workers' exposure to MnO2 (5.3 years) yields a LOAE L of 0.15 mg/cu.m. Th e LOAEL(HEC) is 0.05 mg/cu.m.
Roels et al. (1987) conducted a cross-sectiona l study in 141 male workers exposed to MnO2, manganese tetroxide (Mn3O4), and various Mn salts (sulfate, carbonate, and nitrate). A matched group of 104 male workers was selected as a co ntrol group. The two groups were matched for socioeconomic status and background environmental factors; in addition, both groups had comparable work-load and wo rk-shift characteristics.
The TWA of total airborne Mn dust ranged from 0.07 to 8.61 mg/cu.m, with an overall arithmetic mean of 1.33 mg/cu.m, a median of 0.97 mg/cu.m, and a geomet ric mean of 0.94 mg/cu.m. The duration of employment ranged from 1 to 19 years, with a mean of 7.1 years. The particle size and purity of the dust were no t reported. Neurological examinat ion, neurobehavioral function tests (simple reaction time, short-term memory , eye-hand coordination, and hand tremor), spirographic measurements, blood and urine tests, and a self- ad ministered questionnaire were used to assess possible toxic effects of Mn ex posure. The questionnaire was designed to detect CNS and respiratory symptoms.
Significant differences in mean scores between Mn-exposed and reference subjects were found for objective measures of visual reaction time, eye-hand coordination, hand steadiness, and audio-verbal short-term memory. The prevalence of abnormal sco res on eye-hand coordination and hand steadiness tests showed a dose-response relationship with blood Mn levels; short-term memory scores were related to ye ars of Mn exposure but not to blood Mn levels. The prevalence of subjective symptoms was greater in the expose d group than in controls for 20 of 25 items on the questionnaire, with four items being statistically significant: fatigue, tinnitus, trembling of fingers, and irritability.
A significantly greater prevalence of coughs during the cold seas on, dyspnea during exercise, and recent episodes of acute bronchitis was self- reported in the exposed group. Lung function parameters were only slightly (<10%) lower in the Mn-exposed workers, with the only significant alterations evident in Mn-exposed smokers. Thes e mild changes in Mn-exposed workers (apart 

### http://www.epa.gov/iris/subst/0373.htmfrom the effects of smoking) and the absence of respiratory effects in th e more recent study by Roels et al. (1992) suggestthat the nervous system is a moresensitive target for Mn toxicity.
Based upon the findings of impaired neurobeh avioral function in workers whose average Mn exposure was estimated by the geometric mean TWA of total airborne Mn dust at the time of the study, a LOAEL of 0.97 mg/cu.m wa s identified, with a LOAEL(HEC) of 0.34 mg/cu.m. Note that this LOAEL(HEC) is based on total Mn dust of mixed forms, whereas the LOAEL(HEC) from the more recent Roels et al. (1992) st udy is based on the measured resp irable dust fraction of MnO2 only. However, the geometric mean total dustconcentrations in the 1987 and 1992 studies by Roels et al. were approximately the same (0.94 and 0.95 mg/cu.m, respectively).
The findings of Roels et al. (1987, 1992) are su pported by other recent reports that provide comparable and consistent indications of neurobehavioral dysfunction in Mn-exposed workers (Mergler et al., 1993; Iregren, 1990; Wennberg et al., 1991, 1992).
Mergler et al. (1993) conducted a cross-sect ional study of 115 male ferromanganese and silicomanganese alloy workers in southwest Qu ebec. A matched-pair design was employed because of presumptively high environmental pollutant levels; 74 pairs of workers and referents were matched on age, educational level, smoking status, number of children, and length of residency in the region.
Air concentrations of respirableand total dust were sampled bystationary monitors during silicomanganese producti on. The geometric mean of a seri es of 8-hour TWAs was 0.035 mg Mn/cu.m (range: 0.001-1.273 mg Mn/cu.m) for respirable dust and 0.225 mg Mn/cu.m (range: 0.014-11.480 mg Mn/cu.m) for total dust. The authors noted that past dust levels at certain job sites had been considerably higher. The mean du ration of the workers' Mn exposure was 16.7 years and included Mn fumes as well as mixed oxides and salts of Mn. Geometric mean MnB was significantly higher in the Mn alloy workers, bu t MnU did not differ sign ificantly between exposed workers and controls.
The number of discordant pairs, in which workers reported undesirable symptoms on a selfadministered questionnaire but their matched pairs did not, was statistically significant for 33 of 46 items, including the following: fatigue; emotional state; memory, attention, and concentration difficulties; nightmares; sweating in the absence of physical exertion; sexual dysfunction; lower back pain; joint pain; and tinnitus. Workers did not report symptoms typical of advanced Mn poisoning (e.g., hand tremor, changes in handwritin g, loss of balance when turning, difficulty in reaching a fixed point) significan tly more than referents, which suggests that the other reported symptoms were probably not due to bias on the part of the workers.
The greatest differences in neurobehavioral function were evident in tests of motor function, especially tests requiring coordinated alternating and/or rapi d movements. Workers performed significantly worse on the motor sca le of a neuropsychological testbattery both in overall score and in eight subscales of rapid sequential or alternating moveme nts. Worker performance also was significantly worse on tests of hand steadine ss, parallel-line drawing performance, and ability to rapidly identify and mark specified alphabetic characters within strings of letters. Performance on a variety of other tests of ps ychomotor function, including simple reaction time, was worse in Mn- exposed workers but marginally significant (0.05 < p < 0.10). In addition, Mn alloy workers differed significantly from referents on measures of cognitive flexibility and emotional state. Olfactory perception also was significantly enhanced in the Mn-alloy workers.
The matched-pair design of Merg ler et al. (1993) helped reduce differences between exposed and referent subjects that might otherwise have confounded the study. However, to the extent that 

### http://www.epa.gov/iris/subst/0373.htmthe referents also may have had significant expo sure to Mn in the am bient atmosphere, such exposure may have reduced the differences in neurobehavioral performance between workers and referents. This possibility is supported by the fact that the finger -tapping speed of both workers and referents on a comp uterized test was slower than that of Mn-exposed workers assessed on the same test by Iregren (1990) in Sweden. In the absence of a NOAEL, the LOAEL from the study of Mergler et al. (1993) is base d on the geometric mean respirable dust level (0.035 mg Mn/cu.m), with a LOAEL(HEC) of ap proximately 0.01 mg/cu.m, which is about fivefold lower than the LOAEL(HE C) identified in the stud y by Roels et al. (1992).
Workers exposed to Mn in two Swedish foundries (15 from each plant) were evaluated in a study first reported by Iregren (1990). The exposure toMn varied from 0.02 to 1.40 mg/cu.m (mean = 0.25 mg/cu.m; median = 0.14 mg /cu.m) for 1-35 years (mean = 9. 9 years). Earlier monitoring measurements made in both factories suggested that essentiallyno changes in exposure had occurred in either factory for the preceding 18 ye ars. Each exposed worker was matched for age, geographical area, and type of work to two wo rkers not exposed to Mn in other industries. Neurobehavioral function was assessed by eight computerized tests and two manual dexterity tests. There were significant di fferences between exposed and cont rol groups for simple reaction time, the standard deviation of re action time, and finger-tapping speed of the dominant hand. In addition, digit-span short-term memory, speed of mental addi tion, and verbal (vocabulary) understanding differed si gnificantly between exposed and contro l groups. The difference in verbal understanding suggested that the two groups were not well matched for general cognitive abilities. With verbal performance used as an ad ditional matching criter ion, differences between the groups in simple reaction time, the standard deviation of reaction time, and finger-tapping speed remained statistically significant, despite a decrease in statistical power due to reducing the size of the reference group to 30 workers. Further analyses using verbal test scores as a covariate also indicated that these same three measures of neurobehavioral function were statistically different in exposed and control workers. No significant correlation was found within the exposed group to establish a concentration- response relationship.
Additional reports of neurobehavioral and electrop hysiological evaluations of these same workers have been published byWennberg et al. (1991, 1992). Althou gh none of the latter results achieved statistical si gnificance at p = 0.05, increased frequency of self-reported health symptoms, increased prevalence of abnormal electroencephalograms, slower brain-stem auditory- evoked potential latencies, and slower diadochokinesometric performance were found in the exposed workers. Diadochoki nesis refers to the ability toperform rapidly alternating movements such as supination and pronation of the forear m, and is an indicator of extrapyramidal function (see Ad ditonal Comments/Studies). Also, an increase in P-300 latency, as suggested by these re sults, has been observed in patien ts with parkinsonism according to Wennberg et al. (1991), wh o viewed these results in Mn-expos ed workers as early (preclinical) signs of disturbances similar toparkinsonism. Based on the impa irments in reaction time and finger-tapping speed reported in the Swedish studies (Iregren, 1990; We nnberg et al., 1991, 1992), the LOAEL(HEC) is calculat ed to be 0.05 mg/cu.m. Althou gh numerically the same value as that derived from Roels et al. (1992), the Swedish study measured total dust. However, Wennberg et al. (1991) stated th at the respirable dust level wa s 20- 80% of total dust, which implies that the LOAEL(HEC) from the Swedish studies could be somewhat lower than that from Roels et al. (1992).
All of the above studies taken together provide a consistent pattern of evidence indicating that neurotoxicity is associated with low-level occupa tional Mn exposure. The fact that the speed and coordination of motor function are especially impa ired is consistent with other epidemiological, clinical, and experimental animal evidence of Mn intoxication (see Additional Comments/Studies). Moreover, the LOAEL(HEC)s obtained from th ese studies are not appreciably different. 

### http://www.epa.gov/iris/subst/0373.htmNevertheless, some differences be tween the studies are evident in the durations of exposure and forms of Mn to which workers were exposed. In th e Roels et al. (1992) study, the mean period of exposure was 5.3 years (range: 0.2-17.7 years), an d exposure was limited to MnO2. In the other studies, mixed forms of Mn werepresent, and the mean durations of exposure were longer: 7.1 years in Roels et al. (1987), 9.9 years in Iregre n (1990), and 16.7 years in Mergler et al. (1993). The findings of Mergler et al. (1993) suggest that the LOAEL(HEC) could be at least as low as approximately 0.01 mg/cu.m. However, the variab le concentrations and mixed compounds of Mn to which workers were exposed make it difficult torely primarily upon the findings of Mergler et al. (1993) in deriving the RfC. Ne vertheless, their results provide su pport for the findings of Roels et al. (1992) and suggest that the longer period of exposure (16. 7 years in Mergler et al. (1993) vs. 5.3 years in Roels et al., 1992) may havecontributed to the apparent differences in sensitivity. Although an alyses by Roels et al . (1987, 1992) and Iregren (1990) generally did not indicate that duration of exposure correlated sign ificantly with neurobehavioral outcomes, none of these studies involved average exposures as long as those in the Mergler et al. (1993) study. Also, the oldest worker in the Roels et al. (1992) study wa s less than 50 years old, and the average age in that study was only 31.3 years vs . 34.3 years in Roels et al. (1987), 43.4 years in Mergler et al. (1993), and 46.4 in Iregren (1990). These points sugge st that chronic exposure to Mn and/or interactions with agin g could result in effects at lowe r concentrations than would be detected after shorter periods of ex posure and/or in younger workers.
Based on the findings of neurobehavioral im pairment by Roels etal. (1987, 1992), with supporting evidence from Mergler et al. (1993) and the Swedish reports (Iregren, 1990; Wennberg et al., 1991, 1992), th e LOAEL for derivation of the RfC is 0.15 mg/cu.m, and the LOAEL(HEC) is 0.05 mg/cu.m.

__I.B.3. Uncertainty and Modi fying Factors (Inhalation RfC)
UF — An uncertainty factor of 1000 reflects 10 toprotect sensitiv e individuals, 10 for use of a LOAEL, and 10 for database limitations reflecting both the less-than-chroni c periods of exposure and the lack of developmental data, as well as potential but unquantifi ed differences in the toxicity of different forms of Mn.

MF — None

__I.B.4. Additional Studie s/Comments (Inhalation RfC)
Manganese toxicity varies depending upon the route of exposure. When ingested, Mn is considered to be among the least toxic of the trace elements. In the normal adult, between 3 and 10% of dietary Mn is absorbed. Total body stores normally are controlled by a complex homeostatic mechanism regulating absorption an d excretion. As detail ed in the Uncertainty Factor Text and the Additonal Comments/Studies fo r the oral RfD, toxicity from ingested Mn is rarely observed. However, defici encies of calcium and iron havebeen noted to increase Mn absorption (Mena et al., 1969; Murp hy et al., 1991). Also, Mena etal. (1969) found that anemic subjects absorbed 7.5% of inge sted Mn, whereas normal subjectsabsorbed 3%. Interestingly, manganism patients absorbed 4%, and apparentlyhealthy Mn miners absorbed only 3%. These differences suggest that certai n subpopulations, such as children, pregnant women, elderly persons, iron- or calcium-deficient individuals, an d individuals with liver impairment, may have an increased potential for excessiveMn body burdens due to increased absorption or altered clearance mechanisms, which may be of particul ar importance for those exposed to Mn by multiple routes. 

### http://www.epa.gov/iris/subst/0373.htmAs a route of Mn exposure, the respiratory tract is the most important portal of entry. The inhalation toxicity of Mn is in part a fu nction of particle dosimetry and subsequent pharmacokinetic events. Particle size determines th e site of deposition in the respiratory tract. Generally, in humans, fine mode particles (<2. 5 um) preferentially de posit in the pulmonary region, and coarse mode particle s (>2.5 um) deposit in the tracheobronchial and extrathoracic regions. Those particle s depositing in the extrathoracic and tracheobronchial regions are predominantly cleared by the mu cociliary escalator into the gastrointestinal tract where absorption is quite low (about 3%). Particles deposited in the pulmon ary region are cleared predominantly to the systemic co mpartment by absorption into th e blood and lymph circulation. Disregarding the possibility of counteracting me chanisms, 100% absorption of particles deposited in the pulmonary region is assumed. Another possi ble route of exposure ma y exist. Studies such as those of Perl and Good (1987) and Evans and Hastings (1992) have indi cated that neurotoxic metals such as aluminum and cadmium can be di rectly transported to the brain olfactory bulbs via nasal olfactory pathways (i.e., from extratho racic deposition). The alteration in olfactory perception that Mergler et al. (1993) found in Mn- exposed workers lends support to the speculation that this pathway may also op erate for Mn, which would further complicate understanding of target-site dosimetry.
The human health effects database on Mn does not include quantitative inhalation pharmacokinetics information on the major oxidesof Mn. Two of the studies described in the Principal and Support Studies (Roe ls et al., 1992; Mergler et al., 1993) measured respirable as well as total Mn dust, and one study (Roels et al., 1992) deal t with workers exposed to only one form of Mn, namely MnO2. However, this information does not allow quantitative determinations of the dose delivered to the respiratory tract or estimates of target-site doses. After absorption via the respiratory tract, Mn is transported th rough the blood stream di rectly to the brain, bypassing the liver and the opportun ity for first-pass hepati c clearance. This direct path from the respiratory tract to the brain is the primary reas on for the differential toxicity of inhaled and ingested Mn. Pharmacokinetic analyses based on inhalation of manganese chloride (MnCl2) by macaque monkeys (Newland et al ., 1987) indicated that clearance from the brain was slower than from the respiratory tract and that the rate of clearance depended on the route of exposure. Brain half-times were 223-267 days after inha lation vs. 53 days fo llowing subc utaneous administration (Newland et al., 1987) or 54 days in humans give n Mn intravenousl y (Cotzias et al., 1968). These long half-times were thought to reflect both sl ower clearance of brain stores and replenishment from other orga ns, particularly the respiratory tract. In rats, Drown et al. (1986) also observed slower cleara nce of labeled Mn from brain than from the respiratory tract. Several occupational physicians have reported large individual differences in workers' susceptibility to Mn intoxicati on, which Rodier (1955) speculat ed might be due in part to differences in the ability to clea r particulate Mn from the lung.
The bioavailability of different forms of Mn is another matter for consideration. Roels et al. (1992) noted that geometric mean blood and urinary Mn levels of workers exposed only to MnO2 in their 1992 report were lower (MnB: 0.81 ug/dL; MnU: 0.84 ug/g creatinine) than those of workers exposed to mixed oxides and salts in their 1987 report (MnB: 1.22 ug/dL; MnU: 1.59 ug/g creatine), even though airborne total dust levels were approximately the same (geometric means of 0.94 and 0.95 mg/cu.m, respectively). Mena et al. (1969) obse rved no differe nce between the absorption of 1 um particles of MnCl2 and manganese sesquioxide (Mn2O3) in healthy adults. Drown et al. (1986) found that following intratracheal instillation of MnCl2 and Mn3O4 in rats, the soluble chloride cleared four times faster than the insoluble oxide from the respiratory tract. However, despite this initial difference, after 2 weeks the amounts of labeled Mn in the respiratory tract were similar for the two comp ounds. Recent work byKomura and Sakamoto (1993) comparing different forms of Mn in mouse diet suggested that less soluble forms such as MnO2 were taken up to a significantly greater de gree in cerebral cortexthan the more soluble 

### http://www.epa.gov/iris/subst/0373.htmforms of MnCl2 and manganese acetate [Mn(CH3C OO)2]; however, the corpus striatal binding characteristics of the +4 valence state of Mn in MnO2 were not substantially different from those of the divalent forms in MnCl2, Mn(CH3COO)2, and manganese carbonat e. Different oxidation states of certain metals (e.g., chromium, nickel, mercury) are known to have different toxicities, and some researchers have suggested that endogenous Mn can havequite different roles in Mn neurotoxicity depending on its ox idation state (e.g., Archibald an d Tyree, 1987; Donaldson et al., 1982). There have been unsubstant iated claims that the higher valence states of Mn (Mn+3, Mn+4) and the higher oxides in ores (Mn2O3 and Mn3O4) are more toxic (Oberdoerster and Cherian, 1988). At present, howeve r, insufficient information exists by which to determine the relative toxicities of different fo rms of Mn, and thus, for the purpos e of deriving an RfC for Mn, no distinction is made among various compounds of Mn.

Because Mn is an essential elem ent and is commonly ingested in diet, total Mn exposure is an issue. It would be desirable to know the effective target- site doses and apportion the dose to both the inhalation and oral routes of exposure. However, given the lack of data regarding oral and inhalation pharmacokine tics under environmental cond itions, such quantitative apportionment is not possible at present.
Among the primary effects associated with Mn to xicity from inhalation exposure in humans are signs and symptoms of CNS toxicity. The first me dical description of chronic Mn neurotoxicity (manganism) in workers is generally credited to Couper in the 1830s (NAS, 1973). Al though the course and degree of Mn intoxication can vary greatly among individuals, manganism is generally considered to consist of two or three phases (Rodier, 1955). The first is the psychiatric aspect, which includes disturbances such as excessi ve weeping and laughing, sleep disturbance, irritability, apathy, and anorexia . These symptoms can occur indepe ndently of the second phase, neurological signs. The latter may include ga it disturbances, dysarthria, clumsiness, muscle cramps, tremor, and mask-like faci al expression. In addition, there may be a final stage of Mn intoxication involving symptoms of irreversible dy stonia and hyperflexion of muscles that may not appear until many years after the onset of exposu re (Cotzias et al., 196 8). Cotzias et al. (1976) noted a parallel between these stages of symptomsand the biphasic pattern of dopamine levels over time in the Mn-exposed individuals noted above. Indeed, various specific features of Mn toxicity show biphasic patterns in which there is generally first an increase then a decrease in performance (e.g., a notable increa se in libido followed by impote nce, or excitement followed by somnolence) (Rodier, 1955).
In addition to studies described in the Principa l and Supporting Studies, numerous investigators have reported CNS effects in workers exposed toMn dust or fumes (Sjo egren et al., 1990; Huang et al., 1989; Wang et al., 1989; Badawy and Shakour, 1984; Si egl and Bergert, 1982; Chandra et al., 1981; Saric et al., 1977; Cook et al., 1974; Smyth et al., 1973; Emara et al., 1971; Tanaka and Lieben, 1969; Schuler et al., 1957; Rodier, 1955; Flinn et al., 1941). Limitations in these studies generally preclude describing a qu antitative concentration-response relationship. Exposure information is often quite limited, with inadequate information on the historical pattern of Mn concentrations or on the chemical compositio n and particle size distri bution of the dust. In addition, exposure to other chem icals in the workplace is often not adequately characterized. Despite these limitations, such studies collectively point to neurobehavioral dysfunction as a primary endpoint for Mn toxicity.
The neuropathological bases for manganism have been investigated by many researchers and have indicated the involvement of the corpus striatum and the extrapyramidal motor system (e.g., Archibald and Tyree, 1987; Donaldson and Barbeau, 1985; Donaldson et al., 1982; Eriksson et al., 1987, 1992). Neuropat hological lesions have generall y been associated with the basal ganglia, specifically involving neuronal de generation in the putamen and globus pallidus 

### http://www.epa.gov/iris/subst/0373.htm(e.g., Newland et al., 1987). Brain imaging stud ies (e.g., Wolters et al., 1989; Nelson et al., 1993) more recently have begun to provide additional insight into th e brain structuresinvolved in Mn toxicity.
In terms of the neurochemistry of Mn toxicity, several studies have shown that dopamine levels are affected by Mn exposure in humans, monkeys, and rodents, with various indi cations of an initial increase in dopamine follo wed by a longer term decrease (e .g., Cotzias et al., 1976; Bird et al., 1984; Barbeau, 1984; Brouillet et al., 1993). Some theoriesof Mn neurotoxic ity have focused on the role of excessive Mn in the oxidation of do pamine resulting in free radicals and cytotoxicity (e.g., Donaldson et al., 1982; Barbeau, 1984). In a ddition, the fundamental role of mitochondrial energy metabolism in Mn toxicity has been indicated by the studies of Aschner and Aschner (1991), Gavin et al. (1992), and others. Brouillet et al. (1993) have suggested that the mitochondrial dysfunctional effects of Mn result in various oxidat ive stresses to cellular defense mechanisms (e.g., glutathione) and, secondarily, free radical da mage to mitochondrial DNA. In view of the slow release of Mn from mitochondria (Gavin et al., 1992), such an indirect effect would help account for a progressive loss of function in the absence of ongoing Mn exposure (Brouillet et al., 1993), as Mn toxicity has been known to continue to progress in humans despite the termination of exposure (Cotzias et al., 1968; Rodier, 1955).
Because of the involvement of the dopaminergicsystem and extrapyram idal motor system in both Parkinson's disease and mang anism, symptoms of the two di seases are somewhat similar, and several writers have sugge sted the possibility of a common etiology; however, many neurological specialists make a clear distinction in the etiologies and clinical features of Parkinson's disease and manganism (B arbeau, 1984; Langston et al., 1987).
Another primary endpoint of Mn toxicity has been male reproductive dysfunction, often manifesting in symptoms such as loss of libido, impotence, and similar complaints (e.g., Rodier, 1955; Cook et al., 1974). Some neuropathological ev idence suggests that the hypothalamus is a site of Mn accumulation (Don aldson et al., 1973); thus, dist urbance of the hypothalamicpituitary-gonadal axis hormones might be expected (D eskin et al., 1981) and has been examined in a few occupational st udies. Lauwerys et al. (1985) re ported the results of a fertility questionnaire administered to male factory workers (n = 85) exposed to Mn dust. This study involved the same populati on of workers for which Roels et al. (1987) reported neurobehavioral disturbances. The range of Mn levels in the breathing zone was 0.07-8.61 mg/cu.m, with a median concentration of 0.97 mg /cu.m. Average length of exposu re was 7.9 years (range of 1-19 years). A group of workers (n = 81) with a similar workload was used as a control group. The number of births expected duri ng different age intervals of th e workers (16-25, 26-35, and 36- 45 years) was calculated on the basis of the re productive experience of the control employees during the same period. A decrease in the numb er of children born to workers exposed to Mn dust during the ages of 16-25 and 26-35 was obse rved. No difference in the sex ratio of the children was found. The same ap parent LOAEL(HEC) (0.34 mg/cu.m) that was identified in Roels et al. (1987) for neurobehavioral ef fects is identified in this stud y for human reprod uctive effects.
However, a more recent report from the same group of investigators (Gennart et al., 1992), based on 70 of the alkaline batt ery plant workers evaluated by Ro els et al. (1992), indicated that the probability of live birth was not different be tween the Mn-exposed and control workers. Also, in the study by Roels et al. ( 1992), serum levels of certain hormones related to reproductive function (FSH, LH, and prolactin) were not sign ificantly different for the full group of 92 Mn workers vs. 102 controls. The latter results are pa rtially supported by a preliminary report by Alessio et al. (1989), who found th at serum FSH and LH levels werenot significantl y different in 14 workers generally exposed to <1 mg Mn/cu.m compared to controls, although prolactin and cortisol levels were significantly higher in the Mn -exposed workers. It is possible that differences 

### http://www.epa.gov/iris/subst/0373.htmin the forms of Mn to which workers were expose d in these studies may ha ve contributed to the similarities and differences in the results, but insufficient information exists to substantiate this speculation.
Average concentrations of airborneMn differed slightly in the re ports of Gennart et al. (1992) and Roels et al. (1992), evidently because only a subsetof Mn workers, presum ably with different job functions, was used in the Ge nnart et al. (1992) analysis. The median respirable dust concentration was 0.18 mg/cu.m, and the median total dust concentration (comparable to Roels et al., 1987, and Lauwerys et al., 1985) was 0.71 mg/cu.m. Thus, if 0.34 mg/cu.m is identified as a LOAEL(HEC) based on the repo rts of Lauwerys et al. (1985) and Roels et al. (1987), 0.25 mg/cu.m total dust is the NOAEL(HEC) for reproductive effects based on the report of negative findings by Gennart et al. (1992).
The respiratory system is another primary targ et for Mn toxicity; nu merous reports of Mn pneumonitis and other effects on the respiratory system have appeared in the literature, dating back to 1921 (NAS, 1973). In their cross- sectiona l study of workers exposed to mixed Mn oxides and salts (described in the Principal and Supporting Studies), Roels et al. (1987) found that significantly greater prevalences of coughs during the cold season, dyspnea during exercise, and recent episodes of acute bronchitis were report ed in the exposed group on a self-administered questionnaire. However, objectivelymeasured lung function parameters were only slightly altered and only in Mn- exposed smokers (also see Saric and Lucic-Palaic, 1977, regarding a possible synergism between Mn and smoking in producing respiratory symptoms). In their more recent study, Roels et al. (1992) found no significan t differences between Mn O2-exposed and control workers in responses to a questionnaire regard ing respiratory symptoms. Nor were objective spirometric measurements sign ificantly different for the tw o groups. The LOAEL(HEC) for respiratory effects is 0. 34 mg/cu.m total dust, based on the Roels et al. (1987) study, and the NOAEL(HEC) is 0.05 mg/cu.m respirable dust, based on the Roels et al. (1992) study. In view of the near equivalence of the geometric mean to tal dust concentrations in the 1987 and 1992 studies by Roels et al. (0.94 and 0.95 mg/cu.m, respectively), there in fact may be little difference between the LOAEL(HEC) and the NO AEL(HEC) in terms of air concentrations; however, differences in the forms of Mn (MnO2 vs. mixed Mn oxides and salts) to which the workers in the two studies were ex posed make it difficult to comp are these values quantitatively.
Nogawa et al. (1973) investigated an associatio n between atmospheric Mn levels and respiratory endpoints in junior high school students. A qu estionnaire focusing on eye, nose, and throat symptoms and pulmonary function te sts were given to students attending junior high schools that were 100 m (enrollment = 1258) and 7 km (enro llment = 648) from a ferromanganese plant. Approximately 97-99% of the studen ts participated. Based on meas urements obtained at another time by a government agency, the 5-day averag e atmospheric Mn level 300 m from the plant was reported to be 0.0067 mg/cu.m.
Significant increases in past hi story of pneumonia, eye problems, clogged nose, nose colds, throat swelling and soreness, and other symptomswere noted among the students in the school 100 m from the plant. Those living closest to the plant reported more throat symptoms and past history of pneumonia than did students living fa rther away. Pulmonary fu nction tests revealed statistically significant decreases in maximum expiratory flow, forced vital capacity (FVC), forced expiratory volume at 1 second (FEV-1), and the FVC:FEV- 1 ratio in the students attending the school closer to the plant, with some measures suggesting a re lationship between performance and distance of reside nce from the plant.
Although the results from the study of Nogawa et al. (1973) suggest an association between ambient Mn exposure and respiratory problems, lim itations in the study make it difficult to 

### http://www.epa.gov/iris/subst/0373.htminterpret. No direct measurements were made of atmospheric Mn levels either in the schools or homes, and exposure levels were inferred from the distance from the pl ant and other indirect measures of Mn in the environment. Also, th e authors did not note whether socioeconomic variables were controlled, and this factor could well be confounded with both distance from the plant and health problems. A fo llow-up study by Kagamimori et al. (1973) suggested that, following reductions in Mn emissions (with apparent ly no reduction in sulfur dioxide or total dust) from the ferromanganese plant, st udents nearest the plant showed improvements in subjective symptoms and pulmonary function tests. As before, however, exposure levels were not adequately characterized to allow clear-cut conclusions.
Lloyd-Davies (1946) reported an increased inci dence of pneumonia in men employed at a potassium permanganate manufacturing facility over an 8-year period. During that period, the number of workers in the facility varied from 40 to 124. Dust measurements were well described in terms of collection conditions and particle si ze and composition, but actual exposure levels were not evaluated. Air concentrations rang ed from 9.6 to 83.4 mg /cu.m as MnO2, which constituted 41-66% of the dust . The incidence of pneumonia in the workers was 26 per 1000, compared to an average of 0.73 per 1000 in a reference group of over 5000 workers. Workers also complained of bronchitis and nasal irritation . In a continuation of th is study, Lloyd-Davies and Harding (1949) reported the results of sp utum and nasopharynx cultures for four men diagnosed as having lobar- or bronchopneumonia. With the exceptio n of one of thes e cases, they concluded that Mn dust, without th e presence of bacterial infectio n or other factors, caused the observed pneumonitis.
Evidence from several laboratory animal studie s supports findings in Mn- exposed humans. For example, inhaled Mn has been show n to produce significant alterations in dopamine levels in the caudate and globus pallidus of Rhesus monkey s (Bird et al., 1984) an d behavioral changes in mice (Morganti et al., 1985). However, species differences ma y complicate inte rpretation of certain neurobehavioral findings in laboratory animals. Unlike primates, rodents do not have pigmented substantia nigra, which is a brain region of relatively high Mn uptake and consequent involvement in neurobehavioral dysfunction. Ne vertheless, rodent and primate studies show various neurochemical, neuropathological, and neurobehavioral effects resulting from Mn exposure. However, because most laboratory animal studies of Mn neurotoxicity involve exposure by routes other than inhalation, they are not described here.
Other endpoints of Mn toxicity also have been investigated with laboratory animal models of inhalation exposure. Experimental animal data qualitatively support human study findings of respiratory effects in th at Mn exposure results in increase d incidence of pn eumonia in rats exposed to 68-219 mg/cu.m MnO2 for 2 weeks (Shiotsuka, 1984), pulm onary emphysema in monkeys exposed to 0.7-3.0 mg/c u.m MnO2 for 10 months (Suzuki et al., 1978), and bronchiolar lesions in rats and hamsters exposed to 0.117 mg/cu.m Mn3O4 for 56 days (Moore et al., 1975). Also, Lloyd-Davies and Harding (1949) induced bronchiolar epithelium infl ammation, widespread pneumonia, and granulomatous re actions in rats administered 10 mg MnO2 by intratracheal injection, and pulmonary edema in rats admini stered 5-50 mg MnCl2 in the same fashion. However, no significant pulmonary effects were detected in other studie s of rats and monkeys exposed to as much as 1.15 mg Mn/cu.m as Mn 3O4 for 9 months (Ulrich et al., 1979a,b,c) or rabbits exposed to as much as 3.9 mg Mn/cu. m as MnCl2 for 4-6 weeks (Camner et al., 1985).
Laboratory animal studies also have shown that inhaled Mn may increase susceptibility to infectious agents such as Streptococcus pyogen es in mice (Adkins et al., 1980), Enterobacter cloacae in guinea pigs (Bergstrom , 1977), Klebsiella pneumoniae in mice (Maigetter et al., 1976), and Streptococcus hemolyticus in mice (Lloyd-Davies, 1946). In ge neral, Mn concentrations were relatively high (>10 mg/cu.m) in these studies. However, Adki ns et al. (1980) concluded that, 

### http://www.epa.gov/iris/subst/0373.htmbased on the regression line ofthe relationship between concentration and mortality in Mnexposed mice, exposure to <0.62 mg/cu.m would re sult in a mortality rate that differed from controls by at least 10%.
The developmental effects of Mn have been inve stigated primarily from the viewpoint of the nutritional role of this element and therefore ha ve generally involved oral exposure. Some studies indicate that neonates of various species havea greater body burden of Mn than mature individuals have, possibly because neonates do not develop the ability to eliminate Mn--and thereby maintain Mn homeostasis--u ntil some time after birth (Miller et al., 1975; Cotzias et al., 1976; Wilson et al., 1991). More over, some evidence suggests th at the neonate's inability to maintain Mn homeostasis is due to a limitation in the elimination of Mn rather than in its gastrointestinal absorption ( Bell et al., 1989), which would suggest a potentially greater vulnerability of young individuals to excessive Mn exposure regardless of the route of exposure.

Several studies have demonstrated neurochemica l alterations in young rats and mice exposed postnatally to Mn by routes ot her than inhalation (e.g., Kont ur and Fechter, 1988; Seth and Chandra, 1984; Deskin et al., 1981; Cotzias et al., 1976). The only inhalation study of the developmental toxicity of Mn appears to be that of Lown et al. (1984). Fe male mice were exposed to MnO2 7 hours/day, 5 days/week for 16 weeks prior to conception and for 17 days following conception (i.e., gestational days 1-18). For th e first 12 weeks, the air concentration was 49.1 mg Mn/cu.m; all later exposures were at 85.3 mg Mn/cu.m. To separate prenatal and postnatal exposure effects, a cro ss- fostering design was used. Although mothers exposed to MnO2 prior to conception produced significantly worse pups per litter, prenatally ex posed offspring showed reduced scores on various activitymeasures (open field, roto-rod , and exploration) and retarded growth that persisted into adulth ood. A decrease in roto-rod pe rformance was also observed in the offspring of nonexposed mice that were fostered to Mn-exposed females during lactation. Thus, balance and coordination were affected by either gestational or po stpartum exposure to MnO2.

__I.B.5. Confidence in the Inhalation RfC
Study — Medium Database — Medium RfC — Medium
Confidence in the principal studies (Roels et al., 1987, 1992) is medium. Ne ither of the principal studies identified a NOAEL for neurobehavioral ef fects, nor did either study directly measure particle size or provide information on the part icle size distribution. The 1992 study by Roels et al. did provide respirable and total dust meas urements, but the 1987 stud y measured only total dust. These limitations of the studies are mitigate d by the fact that the principal studies found similar indications of neurobehavioral dysfunction, and these findings were consistent with the results of other human studies (Mergler et al., 1993; Iregren, 1990; Wennberg et al., 1991, 1992; as well as various clinical studies). In addi tion, the exposurehistory of the workers in the 1992 study by Roels et al. was well characteri zed and essentially had not changed over the preceding 15 years, thereby allowing calculation of integrated exposure levels for individual workers. However, individual integrated exposu res were not established in the 1987 study of Roels et al.

Confidence in the database is me dium. The duration of exposure was relatively limited in all of the principal and supporting studie s, ranging from means of 5.3 an d 7.1 years in the co-principal studies by Roels et al. (1992 and 1987, respectively ) to a maximum of 16.7 years in the study by Mergler et al. (1993). Moreover, the workers wererelatively young, ranging from means of 31.3 

### http://www.epa.gov/iris/subst/0373.htmand 34.3 years in the co-principal studies (Roe ls et al., 1992 and 1987, respectively) to a maximum of 46.4 years (Iregren, 1990). These temp oral limitations raise concerns that longer durations of exposure and/or inte ractions with aging might result in the detection of effects at lower concentrations, as suggested by results from studies invol ving longer exposure durations and lower concentrations (Mergler et al., 1993; Iregren, 1990). In addition, except for the 1992 study by Roels et al., in which Mn exposurewas limited to MnO2, the other principal and supporting studies did not specify the species of Mn and the proportions of the different compounds of Mn to which workers were exposed. It is not clear whethe r certain compounds or oxidation states of Mn are more toxic than others. Thus, it is not possible to distinguish the relative toxicity of different Mn compounds in these studies, despite so me indications in the literature regarding the differential toxicity of various oxidation states of Mn. Although the primary neurotoxicological effects of exposure to airborne Mn have been qualitatively well characterized by the general consistency of effects across studies, the exposure-effect relationship remains to be well quantified, and a no-effect level for neurotoxicity has not been identified in any of these studies thus far. Finally, the effects of Mn on development and reproduction have not been studied adequately. Insufficient information on the developmental toxicity of Mn by inhalation exposure exists, an d the same is true for information on female reproductive function. The study of the reproductive toxicity of inhaled Mn in males also needs to be characterize d more fully.
Reflecting medium confidence in the principal studies and medium confid ence in the database, confidence in the inhalation RfC is medium.

__I.B.6. EPA Documentation and Review of the Inhalation RfC
Source Document — This assessment is not presented in any existing U.S. EPA document.

Other EPA Documentat ion — U.S. EPA, 1984
Agency Work Group Review — 08/23/1990, 09/19/1990, 09/23/1993

Verification Date — 09/23/1993
Screening-Level Literature Review Findings — A screening-level review conducted by an EPA contractor of the more recent toxicology literat ure pertinent to the RfC for Manganese conducted in September 2002 identified one or more significant new studies. IRIS users may request the references for those studies from the IRIS Hotline at hotlin e.iris@epa.gov or (202)566-1676.

__I.B.7. EPA Contacts (Inhalation RfC)
Please contact the IRIS Hotline for all questions co ncerning this assessment or IRIS, in general, at (202)566-1676 (phone), (202)566-1749 (FAX) or hotline.iris@epa.gov (internet address).



### _II. Carcinogenicity Asse ssment for Lifetime Exposure
Substance Name — Manganese CASRN — 7439-96-5 Last Revised — 12/01/1996
Section II provides information on three aspects of the carcinogenic assessment for the substance in question; the weight-of-evidence judgment of the likelihood that the substance is a human 

### http://www.epa.gov/iris/subst/0373.htmcarcinogen, and quantitative estimates of risk from oral exposure and from inhalation exposure. The quantitative risk estimates are presented in three ways. The slope factor is the result of application of a low-dose extrap olation procedure and is presente d as the risk per (mg/kg)/day. The unit risk is the quantitative estimate in terms of either risk per ug/L dr inking water or risk per ug/cu.m air breathed. The third form in which ri sk is presented is a drinking water or air concentration providing cancer risks of 1 in 10, 000, 1 in 100,000 or 1 in 1,000,000. The rationale and methods used to develop the carcinogenicity information in IRIS are described in The Risk Assessment Guidelines of 1986 (E PA/600/8-87/045) and in the IRISBackground Document. IRIS summaries developed since the pu blication of EPA's more recent Proposed Guidelines for Carcinogen Risk Assessment also utilize those Guidelines where indicated (Federal Register 61 (79):17960-18011, April 23, 1996). Users are referred to Section I of this IRIS file for information on long-term toxic effects other than carcinogenicity.
NOTE: Manganese is an element cons idered essential to human health.

_II.A. Evidence for Human Carcinogenicity
__II.A.1. Weight-of-Evid ence Characterization
Classification — D; not classifiab le as to human carcinogenicity
Basis — Existing studies are inadequate to assess the carcinogenicity of manganese.

__II.A.2. Human Carcinogenicity Data

None.

__II.A.3. Animal Carcinogenicity Data
Inadequate. DiPaolo (1964) subcutaneously or intrap eritoneally injected DBA/1 mice with 0.1 mL of an aqueous of solution 1% manganese chloridetwice weekly for 6 months. A larger percentage of the mice exposed subcutan eously (24/36; 67%) and intrap eritoneally ( 16/39; 41%) to manganese developed lymphosarcomas compared wi th controls injected with water (16/66; 24%). In addition, tumors appeared earlier in the exposed groups than in the control groups. The incidence of tumors other than lymphosarcomas(i.e., mammary adenocarcinomas, leukemias, injection site tumors) did not differ significan tly between the exposed groups and controls. A thorough evaluation of the re sults of this study was not po ssible because the results were published in abstract form.
Stoner et al. (1976) tested manganous sulfate in a mouse lu ng adenoma screening bioassay. Groups of strain A/Strong mi ce (10/sex), 6-8 weeks old, were exposed by intraperitoneal injection to 0, 6, 15 or 30 mg/kg manganous su lfate 3 times/week for 7 weeks (a total of 21 injections). The animals were obse rved for an additional 22 weeks after the dosing period, before sacrifice at 30 weeks. Lung tumo rs were observed in 12/20, 7/20 , and 7/20 animals in the high, medium, and low dosage groups, respectively. The percentage of mice with tumors was elevated, but not significantly, at the highest dose level (F isher Exact test) compared with that observed in the vehicle controls. In addition , there was an apparent increa se in the average number of pulmonary adenomas per mouse both at the mid and high doses, as compared with the vehicle controls (10 mice/sex), but the in crease was significant only at th e high dose (Student's t-test, p<0.05). 

### http://www.epa.gov/iris/subst/0373.htmIn the mouse lung adenoma bioassay, certain spec ific criteria should be met in order for a response to be considered positive (Shimkin and Stoner, 1975). Among these criteria are an increase in the mean number of tumors per mouse and an evid ent dose-response relationship. While the results of this study are suggestive of carcinogenicity, the data cannot be considered conclusive since the mean number of tumors per mouse was si gnificantly increased at only one dose, and the evidence for a dose-response relationship was marginal.
Furst (1978) exposed groups of F 344 rats (25/sex) intramuscularl y or by gavage to manganese powder, manganese dioxide, and manganese (II) acetylacetonate (MAA). Treatment consisted of either 9 i.m. doses of 10 mg ea ch of manganese powder or ma nganese dioxide, 24 doses of 10 mg manganese powder by gavage, or 6 i.m. dose s of 50 mg of MAA. In addition, female swiss mice (25/group) were exposed intramuscularly to manganese powder (single 10 mg dose) and manganese dioxide (6 doses of 3 or 5 mg ea ch). There was an increased incidence of fibrosarcomas at the injection site in male (40% ) and female (24%) rats exposed intramuscularly to MAA compared with vehicle co ntrols (4% male, 4% female). EPA (1984) determin ed that these increases were statistically significant and noted that the study results re garding MAA, an organic manganese compound, cannot necessarily be extrap olated to pure manganese or other inorganic manganese compounds. No difference in tumo r incidence was found between rats and mice exposed to manganese powder and manganese dioxid e and controls.
Sunderman et al. (1974, 1976) exposed male 344 rats to 0.5 to 4.4 mg manganese dust intramuscularly and found that no tumors were induced at the injection site. It was further observed that co-administration of manganese wi th nickel subsulfide resulted in decreased sarcoma production by comparison to nickel subs ulfide alone. Subsequentstudies by Sunderman et al. (1980) suggest that manganese dust ma y inhibit local sarcoma induction by benzo(a) pyrene.
Witschi et al. (1981) exposed female A/J mice intraperitoneally to 80 mg/kg methylcyclopentadienyl manganese tricarbonyl (MMT ) and found that althou gh cell proliferation was produced in the lungs, lung tumor incidence did not increase.

__II.A.4. Supporting Data for Carcinogenicity

None.

_II.B. Quantitative Estimate of Carcin ogenic Risk from Oral Exposure

Not available.

_II.C. Quantitative Estimate of Carcinog enic Risk from Inhalation Exposure

Not available.

_II.D. EPA Documentation,Review, and Contacts (C arcinogenicity Assessment)

__II.D.1. EPA Documentation
Source Document — U.S. EPA, 1984, 1988 

### http://www.epa.gov/iris/subst/0373.htmThe Drinking Water Criteria Document fo r Manganese has received OHEA review.

__II.D.2. EPA Review (Carcinogenicity Assessment)
Agency Work Group Review — 05/25/1988
Verification Date — 05/25/1988
Screening-Level Literature Review Findings — A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the cancer assessment for Manganese conducted in September 2002 did not identify any critical new studies. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or (202)566-1676.

__II.D.3. EPA Contacts (Carcinogenicity Assessment)
Please contact the IRIS Hotline for all questions co ncerning this assessment or IRIS, in general, at (202)566-1676 (phone), (202)566-1749 (FAX) or hotline.iris@epa.gov (internet address).



### _III. [reserved] _IV. [reserved] _V. [reserved]

_VI. Bibliography
Substance Name — Manganese CASRN — 7439-96-5 Last Revised — 11/01/1995

_VI.A. Oral RfD References
Aschner, M. and J.L. Aschner. 1991. Manganese neurotox icity: Cellular effects and blood-brain barrier transport. Neurosci. Behav. Rev. 15: 333- 340.
Banta, R.G. and W.R. Markesbery . 1977. Elevated manganese leve ls associated with dementia and extrapyramidal signs. Neurology. 27: 213-216.
Barlow, P.J. and M. Kapel. 1979. Hair metal anal ysis and its significan ce to certain disease conditions. 2nd Ann. Trace Minerals Health Seminar, Boston, MA.
Cawte, J. and M.T. Florence. 1989. A manganic milieu in Nort h Australia: Ecological manganism: Ecology; diagnosis; individual susceptibility; synergism; therapy; prevention; advice for the community. Int. J. Biosocia l Med. Res. 11(1): 43-56.
Chandra, S.V. and G.S. Shukla. 1981. Concentrations of striatal catecholamines in rats given manganese chloride throug h drinking water. J. Neurochem. 36(2): 683-687.
Collipp, P.J., S.Y. Chen and S. Maitinsky. 1983. Manganese in infant formulas and learning disability. Ann. Nutr . Metab. 27: 488-494. 

### http://www.epa.gov/iris/subst/0373.htmDavidsson, L., A. Cederblad, B. Lonnerdal and B. Sandstrom. 1989 . Manganese retention in man: A method for estimating manganese absorpti on in man. Am. J. Clin. Nutr. 49: 170-179.
Devenyi, A.G., T.F. Barron and A.C. Mamourian. 1994. Dyston ia, hyperintense basal ganglia, and high whole blood manganese leve ls in Alagille's syndrome. Ga stroenterology. 106(4): 1068-1071.
Doisy, E.A., Jr. 1972. Micron utrient controls on bios ynthesis of clotting proteins and cholesterol. In: Trace Substances in Environmental Health Vol. VI. D.D. Hemphill, Ed. University of Missouri, Columbia, MO. p. 193-199.
Donaldson, J. 1987. The physiopathologic significance of manganese in brain: Its relation to schizophrenia and neurodegen erative disorders. Neurotoxicology. 8(3): 451-462.
Ejima, A., T. Imamura, S. Nakamura, H. Sait o, K. Matsumoto and S. Momono. 1992. Manganese intoxication during total parenteral nutrition. Lancet. 339: 426.
Florence, T.M. and J.L. Stauber. 1989. Manganese catalysis of dopamine oxidation. Sci. Total Environ. 78: 233-240.
Freeland-Graves, J. and C. Ll anes. 1994. Models to study mang anese deficiency. In: Manganese in Health and Disease, D.J. Klimis-Tavantzis, Ed. CRC Press, Boca Raton, LA. p. 59-86.
Freeland-Graves, J.H., C.W. Bales and F. Behma rdi. 1987. Manganese requirements of humans. In: Nutritional Bioavailability of Manganese, C. Kies, Ed. American Chemic al Society, Washington, DC. p. 90-104.
Friedman, B.J., J.H. Freeland-Gra ves, C.W. Bales, et al. 1987. Manganese balance and clinical observations in young men fed a manganese-deficient di et. J. Nutr. 117(1): 133-143.
Gottschalk, L.A., T. Rebello, M. S. Buchsbaum, H.G. Tucker and E.L. Hodge s. 1991. Abnormalities in hair trace elements as indicators of abe rrant behavior. Compr. Psychiatry. 32(3): 229-237.
Gupta, S.K., R.C. Murthy and S.V. Chandra. 1980. Ne uromelanin in manganese- exposed primates. Toxicol. Lett. 6: 17-20.
Kawamura, R., H. Ikuta, S. Fuku zumi, et al. 1941. Intoxication by manganese in well water. Kitasato Arch. Exp. Med. 18: 145-169.
Keen, C.L. and S. Zide nberg-Cherr. 1994. Manganese toxicity in humans and experimental animals. In: Manganese in Health and Disease, D.J. Klimis- Tava ntzis, Ed. CRC Press, Boca Raton, LA. p. 194-205.
Kies, C. 1987. Manganese bi oavailability overview. In: Nutritiona l Bioavailability of Manganese, C. Kies, Ed. ACS Symposium Series 354, Americ an Chemical Society, Washington, DC.
Kilburn, C.J. 1987. Manganese, malformation an d motor disorders: Findings in a manganese exposed population. Neurotoxicology. 8(3): 421-430.
Komura, J. and M. Sakamoto. 1991. Short-term oral administration of several manganese compounds in mice: Physiologica l and behavioral alterations ca used by different forms of manganese. Bull. Environ. Contam. Toxicol. 46: 921-928. 

### http://www.epa.gov/iris/subst/0373.htmKondakis, X.G. 1990. Profe ssor, University of Patras, Greece. Le tter to S. Velazquez, U.S. EPA, Cincinnati, OH. August 23.
Kondakis, X.G. 1993. Profe ssor, University of Patras, Greece. Le tter to S. Velazquez, U.S. EPA, Cincinnati, OH. June 7.
Kondakis, X.G., N. Makris, M. Leotsinidis, M. Prin ou and T. Papapetropoulos. 1989. Possible health effects of high manganese concentration in drinking water. Arch. Environ. Health. 44(3): 175-178.
Lai, J.C.K., T.K.C. Leung and L. Lim. 1981. Brain regional di stribution of glutamic acid decarboxylase, choline acetyltrans ferase, and acetylcholinesterase in the rat: Effects of chronic manganese chloride administ ration after two years. J. Neurochem. 36(4): 1443-1448.
Lai, J.C.K., T.K.C. Leung, J.F. Guest, A.N. Davison and L. Li m. 1982. The effects of chronic manganese chloride treatment expressed as ag e-dependent, transient changes in rat brain synaptosomal uptake of amines . J. Neurochem. 38(3): 844-847.
Leung, T.K.C., J.C.K. Lai and L. Lim. 1981. The regional dist ribution of mo noamine oxidase activities towards different substrates: Effects in rat brain of chronic administration of manganese chloride and of aging. J. Neurochem. 36(6): 2037-2043.
Lonnerdal, B. 1994. Manganese nutrition of infant s. In: Manganese in Heal th and Disease, D.J. Klimis-Tavantzis, Ed. CRC Press, Boca Raton, LA. p. 175- 191.
Lonnerdal, B., C.L. Keen, J.G. Bell and B. Sandstrom. 1987. Ma nganese uptake and retention: Experimental animal and human stud ies. In: Nutritional Bioavailability of Manganese, C. Kies, Ed. ACS Symposium Series 354, American Chem ical Society, Wash ington, DC. p. 9-20.
Marsden, C.D. and P.G. Jenner. 1987. Th e significance of 1-methyl-4-phenyl1,2,3,6-tetrahydropyridi ne. In: Selective Neuronal Death. Ciba Foundation Symposium 126. Wiley, Chichester. p. 239-256.
McLeod, B.E. and M.F. Robinson. 1972. Metabolic balance of manganese in young women. Br. J. Nutr. 27(1): 221-227.
Mena, I. 1974. The role of manganese in human disease. Ann. Clin. Lab. Sci. 4(6): 487-491.
NRC (National Research Council). 1989. Recomme nded Dietary Allowanc es, 10th ed. Food and Nutrition Board, National Rese arch Council, National Academ y Press, Washington, DC. p. 230- 235.
Pihl, R.O. and M. Parkes. 1977. Ha ir element content in learning disabled children. Science. 198: 204-206.
Ruoff, W.L. 1995. Relative bioavailability of manganese ingested in food or water. In: Proceedings: Workshop on the Bioavailability and Oral Toxicity of Manganese. Sponsored by the U.S. Environmental Protection Agency , Cincinnati, OH, August 30-31, 1994.
Stauber, J.L., T.M. Florence and W.S. Webster. 1987. The use of scalp hair to monitor manganese in Aborigines from Groote Eyland t. Neurotoxicolog y. 8(3): 431-436. 

### http://www.epa.gov/iris/subst/0373.htmU.S. EPA. 1984. Health As sessment Document for Ma nganese. Office of He alth and Environmental Assessment, Environmental Criteria and Asse ssment Office, Cincinna ti, OH. EPA/600/8-83/013F. NTIS PB84-229954.
Wedler, F.C. 1994. Biochemical and nutritional ro le of manganese: An overview. In: Manganese in Health and Disease, D.J. Kllimis-Tavantzis, Ed. CRC Press, Boca Raton, LA. p. 1-37.
WHO (World Health Organization). 1973. Trace El ements in Human Nutritio n: Manganese. Report of a WHO Expert Committee. Tech nical Report Service, 532, WH O, Geneva, Switzerland. p. 34- 36.

_VI.B. Inhalation RfC References
Adkins, B., Jr., G.H. Luginbuh l, F.J. Miller, and D.E. Gardner. 1980. Increased pulmonary susceptibility to streptococcal infe ction following inhalation of manganese oxide. Environ. Res. 23: 110-120.
Alessio, L., P. Apostoli, A. Fe rioli, and S. Lombardi. 1989. Interference of manganese on neuroendocrinal system in exposed workers. Preliminary report. Biol. Trace Element Res. 21: 249-253.
Archibald, F.S. and C. Tyree. 1987. Manganese poisoning and the attack of trivalent manganese upon catecholamines. Arch. Bi ochem. Biophys. 256: 638-650.
Aschner, M. and J.L. Aschner. 1991. Manganese neurotox icity: Cellular effects and blood-brain barrier transport. Neurosci. Biobehav. Rev. 15: 333- 340.
Badawy, A.B.N. and A.A. Shakour. 1984. Ch ronic manganese intoxication (neurological manifestations). In: Proceedings of 5th International Symposium: Trace Elements in Man and Animals. p. 261-263.
Barbeau, A. 1984. Manganese and extrapyramid al disorders. Neurotoxicology. 5: 13-35.
Bell, J.G., C.L. Keen, and B. Loen nerdal. 1989. Higher retention of manganese in suckling than in adult rats is not due to maturational differences in manganese uptake by rat small intestine. J. Toxicol. Environ. He alth. 26: 387-398.
Bergstrom, R. 1977. Acute pulmon ary toxicity of manganese dioxid e. Scand. J. Work Environ. Health. 3: 1-40.
Bird, E.D., A.H. Anton, and B. Bu llock. 1984. The effect of mangan ese inhalation on basal ganglia dopamine concentrations in rhesus monkey. Neurotoxicology. 5(1): 59-65.
Brouillet, E.P., L. Shinobu, U. McGarvey, F. Ho chberg, and M.F. Beal. 1993. Manganese injection into the rat striatum produces excitotoxic lesion s by impairing energy me tabolism. Exp. Neurol. 120: 89-94.
Camner, P., T. Curstedt, C. Jarstrand, A. Johannsson, B. Robertso n, and A. Wiern ik. 1985. Rabbit lung after inhalation of manganese chloride: A comparison with the effects of chlorides of nickel, cadmium, cobalt, and copper . Environ. Res. 38: 301-309. 

### http://www.epa.gov/iris/subst/0373.htmChandra, S.V., G.S. Shukla, R.S. Strivastava, H. Singh, and V. P. Gupta. 1981. An exploratory study of manganese exposure to we lders. Clin. Toxi col. 18(4): 407-416.
Cook, D.G., S. Fahn, an d K.A. Brait. 1974. Chronic manganes e intoxication. Arch. Neurol. 30: 59- 64.
Cotzias, G.C., K. Horiuchi, S. Fuenzalida, an d I. Mena. 1968. Chronic manganese poisoning: Clearance of tissue manganese concentrations wi th persistence of the neurological picture. Neurology. 18: 376-382.
Cotzias, G.C., S.T. Miller, P.S. Papavasiliou, and L.C. Tang. 1976. Interactions between manganese and brain do pamine. Med. Clin. No rth Am. 60(4): 729-738.
Deskin, R., S.J. Bursian, and F. W. Edens. 1981. The effect of ch ronic manganese administration on some neurochemical and physiological variab les in neonatal rats. Gen. Pharmacol. 12: 279- 280.
Donaldson, J., T. St. Pierre, J.L. Minnich, an d A. Barbeau. 1973. Dete rmination of Na+, K+, Mg2+, Cu2+, Zn2, and Mn2 in rat brain regions. Can. J. Biochem. 51: 87-92.
Donaldson, J., D. McGregor, and F. LaBella. 198 2. Manganese neurotoxicity: A model for free radical mediated neurodegeneration? Can. J. Physiol. Pharmacol. 60: 1398-1405.
Donaldson, J. and A. Barbeau. 1985. Manganese ne urotoxicity: Possible clue s to the etiology of human brain disorders. In: Metal Ions in Neurology and Psychiatry, S. Gabay, J. Harris, and B.T. Ho, eds. Alan R. Liss, In c., New York, NY. p. 259-285.
Drown, D.B., S.G. Oberg, and R. P. Sharma. 1986. Pulmonary clea rance of soluble and insoluble forms of manganese. J. Toxicol . Environ. Health. 17: 201-212.
Emara, A.M., S.H. El-Ghawabi, O.I. Madkour, and G.H. El-Samra. 1971. Chronic manganese poisoning in the dry battery industry. Br. J. Ind. Med. 28: 78-82.
Eriksson, H., K. Magiste, L.-O. Plantin et al. 1987. Effects of manganese oxide on monkeys as revealed by a combined neurochemical, histolog ical and neurophysiolog ical evaluation. Arch. Toxicol. 61: 46-52.
Eriksson, H., J. Tedroff, K.A. Thuomas et al. 1992. Manganese induced brain lesions in Macca fascicularis as revealed by po sitron emissions tomography an d magnetic resonance imaging. Arch. Toxicol. 66: 403-407.
Evans, J. and L. Hastings. 1992. Accumulation of Cd(II) in the CNS depending on the route of administration: Intraperit oneal, intratracheal, or intranas al. Fund. Appl. Toxicol. 19: 275-278.
Flinn, R.H., P.A. Neal, and W.B. Fulton. 1941. Industrial manganese pois oning. J. Ind. Hyg. Toxicol. 23(8): 374-387.
Gavin, C.E., K.K. Gunter, and T.E. Gunter. 1992. Mn2+ seques tration by mitochondria and inhibition of oxidative ph osphorylation. Toxicol. A ppl. Pharmacol. 115: 1-5. 

### http://www.epa.gov/iris/subst/0373.htmGennart, J.-P., J.-P. Buchet, H. Roels, P. Ghyselen, E. Ceul emans, and R. Lauwerys. 1992. Fertility of male workers expose d to cadmium, lead, or mangan ese. Am. J. Epidemiol. 135(11): 1208-1219.
Huang, C.-C., N.-S. Chu, C.-S. Lu et al. 1989. Chronic manganes e intoxication. Arch. Neurol. 46 (10): 1104-1106.
Iregren, A. 1990. Psycholo gical test performance in foundry workers exposed to low levels of manganese. Neurotoxicol. Teratol. 12: 673-675.
Kagamimori, S., T. Makino, Y. Hiramaru et al . 1973. [Studies concerning the effects on the respiratory organs of atmospheric pollution caus ed by dusts consisting mainly of manganese. (Report No. 2). On the changes in the effects on the human organism after the environment has been improved]. Nippon Kosh u Eisei Zasshi. 20: 413-421.
Komura, J. and M. Sakamoto. 1993. Subcellula r and gel chromatographic distribution of manganese in the mouse brain: Relation to the ch emical form of chronically-ingested manganese. Toxicol. Lett. 66: 287-294.
Kontur, P.J. and L.D. Fechter. 1988. Brain regional manganese le vels and monoamine metabolism in manganese-treated neonatal rats . Neurotoxicol. Teratol. 10: 295-303.
Langston, J.W., I. Irwin, and G.A. Ricaurte. 1987. Neurotoxins, parkin sonism, and Parkinson's disease. Pharmacol. Ther. 32: 19-49.
Lauwerys, R., H. Roels, P. Genet , G. Toussaint, A. Bouckaert, and S. de Cooman. 1985. Fertility of male workers exposed to mercury vapor or tomanganese dust: A questionnaire study. Am. J. Ind. Med. 7: 171-176.
Lloyd-Davies, T.A. 1946. Manganese pneumo nitis. Br. J. Ind. Med. 3: 111-135.
Lloyd-Davies, T.A. and H.E. Harding. 1949. Manganese pneu monitis: Further clinical and experimental observ ations. Br. J. Ind. Med. 6: 82-90.
Lown, B.A., J.B. Morganti, R. D' Agostino, C.H. Stineman, and E. J. Massaro. 1984. Effects on the postnatal development of the mouse of preconcept ion, postconception and/ or suckling exposure to manganese via maternal inhala tion exposure to MnO2 dust. Neurotoxicology. 5(1): 119-131.
Maigetter, R.Z., R. Ehr lich, J.D. Fenters, and D.E. Gardner. 1976. Potentiating effects of manganese dioxide on experimental respirat ory infections. Enviro n. Res. 11: 386-391.
Mena, I., K. Horiuchi, K. Burke, and G.C. Cotzias. 1969. Chronic manganese poisoning: Individual susceptibility and absorption of iron. Neurology. 19: 1000-1006.
Mergler, D., G. Huel, R. Bowl er et al. 1993. Nervous system dysfunction amon g workers with long-term exposure to manganes e. Environ. Res. (In press)
Miller, S.T., G.C. Cotzias, and H.A. Evert. 1975. Control of tissue manganese: Initial absence and sudden emergence of excretion in the neonatal mouse. Am. J. Physiol. 229(4): 1080-1084.
Moore, W., D. Hysell, R. Miller et al. 1975. Exposure of labo ratory animals to atmospheric manganese from automo tive emissions. Envi ron. Res. 9: 274-284. 

### http://www.epa.gov/iris/subst/0373.htmMorganti, J.B., B.A. Lown, C.H. Stineman, R.B. D'Agostino, and E.J. Massaro. 1985. Uptake, distribution and behavioral effects of inhalation exposure to manganese (MnO2) in the adult mouse. Neurotoxicol ogy. 6(1): 1-16.
Murphy, V.A., J.M. Rosenberg, Q.R. Smith, and S.I. Rapoport. 1991. Elevation of brain manganese in ca lcium-deficient rats. Ne urotoxicology. 12: 255-264.
NAS (National Academy of Scienc es). 1973. Manganese. National Academy of Sciences Printing and Publishing Offi ce, Washington, DC.
Nelson, K., J. Golnick, T. Korn , and C. Angle. 1993. Manganese en cephalopathy: Utility of early magnetic resonance imaging. Br. J. Ind. Med. 50: 510-513.
Newland, M.C., C. Cox, R. Hamada, G. Oberdo erster, and B. Weiss. 1987. The clearance of manganese chloride in the primate. Fund. Appl. Toxicol. 9: 314-328.
Nogawa, K., E. Kobayashi, M. Sakamoto et al. 1973. [Studies of the effe cts on the respiratory organs of air pollution consisting of dusts composed mainly of manganese. (First report). Effects on the respiratory organs of junior high school students]. Nippon Koshu Eisei Zasshi. 20(6): 315- 325.
Oberdoerster, G. and G. Cherian. 1988. Manganes e. In: Biological monito ring of toxic metals, T.W. Clarkson, L. Friberg, G.F. Nordberg, and P. R. Sager, eds. Plenum Press, New York, NY. p. 283-301.
Perl, D.P. and P.F. Good. 1987. Uptake of aluminum into cent ral nervous system along nasalolfactory pathways. Lancet. (8540): 1028.
Rodier, J. 1955. Manganese poisoning in Moro ccan miners. Br. J. Ind. Med. 12: 21-35.
Roels, H. 1993. Correspondence from H. Roels, Faculte de Medecine, Un ite de Toxicologie et Medecine du Travail, CatholiqueUniversite de Louvain, Clos Chapelle-aux-Champs 30, BTE 3054, 1200 Bruxelles, Belgium, to J. Michael Davis, Environmental Crit eria and Assessment Office (MD52), U.S. EPA, Research Triang le Park, NC 27711, October 19.
Roels, H., R. Lauwerys, J.-P. Buchet et al. 1987. Epidemiological survey among workers exposed to manganese: Effects on lung, ce ntral nervous system, and some bi ological indices. Am. J. Ind. Med. 11: 307-327.
Roels, H.A., P. Ghyselen , J.P. Buchet, E. Ceulemans, and R. R. Lauwerys. 1992. Assessment of the permissible exposure level to ma nganese in workers exposed to manganese dioxide dust. Br. J. Ind. Med. 49: 25-34.
Saric, M. and S. Lucic-Palaic. 1977. Possible synergism of exposu re to airborne manganese and smoking habit in occurrence of respiratory sympto ms. In: Inhaled Particles, IV, W.H. Walton, ed. Pergamon Press, New York, NY. p. 773-779.
Saric, M., A. Markicevic, and O. Hrustic. 1977. O ccupational exposure to manganese. Br. J. Ind. Med. 34: 114-118.
Schuler, P., H. Oyanguren, V. Maturana et al. 1957. Manganes e poisoning: Environmental and medical study at a Chilean mine . Ind. Med. Surg. 26: 167-173. 

### http://www.epa.gov/iris/subst/0373.htmSeth, P.K. and S.V. Chandra. 1984. Neurotransmitters and ne urotransmitter receptors in developing and adult rats during manganese poisoning. Neurotoxicology. 5(1): 67-76.
Shiotsuka, R.N. 1984. Inhalation toxicity of manganese dioxide and a magnesium oxidemanganese dioxide mixture. Inhalation Toxicolo gy Facility, Brookhaven National Laboratory, Upton, NY. BNL 35334.
Siegl, von P. and K.-D. Bergert. 1982. Eine fruhdiagnostische Uberwachsungsmethode bei Manganexposition. Z. Ges. Hyg. 28: 524-526.
Sjoegren, B., P. Gustav sson, and C. Hogstedt. 1990. Neuropsy chiatric symptomsamong welders exposed to neurotoxic metals. Br. J. Ind. Med. 47: 704-707.
Smyth, L.T., R.C. Ruhf, N.E. Wh itman, and T. Dugan. 1973. Clin ical manganism and exposure to manganese in the production an d processing of ferromanganese alloy. J. Occup. Med. 15: 101- 109.
Suzuki, Y., N. Fujii, H. Yano, T. Ohkita, A. Ichikawa, and K. Nishiyama. 1978. Effects of the inhalation of manganese dioxid e dust on monkey lu ngs. Tokushima J. Ex p. Med. 25: 119-125.
Tanaka, S. and J. Lieben. 1969. Manganese pois oning and exposure in Pennsylvania. Arch. Environ. Health. 19: 674-684.
Ulrich, C.E., W. Rinehart, and W. Busey. 1979a. Evaluation of the chronic inhalation toxicity of a manganese oxide aerosol. I--Introduction, experi mental design, and aeroso l generation methods. Am. Ind. Hyg. Asso c. J. 40: 238-244.
Ulrich, C.E., W. Rinehart , W. Busey, and M.A. Dorato. 1979b. Ev aluation of the chronic inhalation toxicity of a manganese oxide aerosol. II--Clinica l observations, hematology, clinical chemistry and histopathology. Am. Ind. Hyg. Assoc. J. 40: 322-329.
Ulrich, C.E., W. Rinehart, and M. Brandt. 1979c. Evaluation of th e chronic inhalation toxicity of a manganese oxide aerosol. III--Pulmonary functi on, electromyograms, li mb tremor, and tissue manganese data. Am. Ind. Hy g. Assoc. J. 40: 349-353.

U.S. EPA. 1984. Health As sessment Document for Ma nganese. Final Report. Office of Health and Environmental Assessment, Environmental Criter ia and Assessment Office, Cincinnati, OH. EPA/600/8-83/013F.
Wang, J.-D., C.-C. Huang, Y.-H. Hwang, J.-R. Chiang, J.-M. Lin, and J.-S. Chen. 1989. Manganese induced parkinsonism: An outbreak due to an unrepaired ventilation control system in a ferromanganese smelter. Br . J. Ind. Med. 46: 856-859.
Wennberg, A., A. Iregren, G. Struwe, G. Ci zinsky, M. Hagman, an d L. Johansson. 1991. Manganese exposure in steel smel ters a health hazard to the ne rvous system. Scand. J. Work Environ. Health. 17: 255-262.
Wennberg, A., M. Hagman, and L. Johansson. 1992. Preclinical neurophysiological signs of parkinsonism in occupational manganes e exposure. Neurotoxicology. 13: 271-274.
Wilson, D.C., T.R. J. Tubman, H.L. Halliday, and D. McMa ster. 1991. Plasma manganese levels in the very low birth weight infant are high in early life. Biol. Neonate. 61: 42-46. 

### http://www.epa.gov/iris/subst/0373.htmDate Section Description Wolters, E.Ch., C.-C. Huang, C. Clark et al. 1989. Positron emis sion tomography in manganese intoxication. Ann. Ne urol. 26(5): 647-650.

_VI.C. CarcinogenicityAssessment References
DiPaolo, J.A. 1964. The potentiation of lymphosa rcomas in mice by manganous chloride. Fed. Proc. 23: 393. (Abstract).
Furst, A. 1978. Tumorigenic e ffect of an organomanganese compound on F344 rats and Swiss albino mice: brief commu nication. J. Natl. Cancer Inst. 60(5): 1171-1173.
Shimkin, M.B. and G.D. Stoner. 1975. Lung tumors in mice : Application to carcinogenesis bioassay. Adv. Cancer Res. 21: 1-58.
Stoner, G.D., M.B. Shim kin, M.C. Troxell, T. L. Thompson and L.S. Terry. 1976. Test for carcinogenicity of metallic compounds by the pulm onary tumor response in strain A mice. Cancer Res. 36: 1744-1747.
Sunderman, F.W., Jr., T.J. Lau and L.J. Cralle y. 1974. Inhibitory effe ct of manganese upon muscle tumorige nesis by nickel subsulfide. Cancer Res. 34: 92-95.
Sunderman, F.W., Jr., K.S. Kasprzak, P.P. Minghetti, R.M. Maenza, N. Becker, C. Onkelinx and P.J. Goldblatt. 1976. Effects of manganese on carcino- genici ty and metaboli sm of nickel subsulfide. Cancer Res. 36: 1790-1800.
Sunderman, F.W., Jr., M.C. Reid, P.R. Allpass and S.B. Taubman. 1980. Ma nganese inhibition of sarcoma induction by benzo(a)py rene in Fischer rats. Proc. Am . Assoc. Cancer Res. 21: 72. (Abstract)

U.S. EPA. 1984. Health Assess ment Document for Manganese. Office of Research and Development, Office of Health and Environm ental Assessment, Enviro nmental Criteria and Assessment Office, Cincinnati , OH. EPA 600/8-83- 013F.
U.S. EPA. 1988. Drinking Water Cr iteria Document for Manganese. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washin gton, DC. ECAO-C IN-D008. (External Review Draft).
Witschi, H.P., P.J. Hakkinen and J.P. Kehrer. 1981. Modification of lung tumor development in A/J mice. Toxicolog y. 21: 37-45.



### _VII. Revision History
Substance Name — Manganese CASRN — 7439-96-5

09/26/1988 II. Carcinogen summary on-line 09/01/1989 VI. Bibliography on-line 

### http://www.epa.gov/iris/subst/0373.htm06/01/199 0 I.A

. Oral RfD now under review 08/01/1990 I.A. Oral RfD summary on-line 08/01/1990 II. Text edited 08/01/1990 VI. Oral RfD references added 09/01/1990 I.B. Inhalation RfC now under review 12/06/1990 I.B. Inhala tion RfC on-line 12/06/1990 VI.B. Inhalation RfC references added 01/01/1992 IV. Regulatory Action section on-line 06/01/1992 VI.B. Iregren, 1990 and Nish iyama et al., 1975 pages corrected 08/01/1992 I.A. Oral RfD noted as pending change 08/01/1992 I.A.6. Work group review date added 10/01/1992 I.A. Oral RfD withdrawn; new summary in preparation 10/01/1992 I.A.6. Work group review date added 10/01/1992 VI.A. Oral RfD references withdrawn 01/01/1993 I.A. Oral RfD replaced (RfD changed) 01/01/1993 VI.A. Oral RfD references replaced 05/01/1993 I.A. Work group review date added 07/01/1993 II.A.3. 'Inadequate' added to 1st paragraph 07/01/1993 II.D.1. EPA Docu mentation clarified 11/01/1993 I.B. Inhalation RfC noted as pending changed 11/01/1993 I.B.6. Work group review date added 12/01/1993 I.B. Inhalation RfC replaced; RfC changed 12/01/1993 VI.B. Inhalation RfC references replaced 01/01/1994 I.A. Oral RfD noted as pending change 01/01/1994 I.A.6. Work group review date added 03/01/1994 II.D.3. Primary contact changed 04/01/1994 I.A.2. Text revised 04/01/1994 I.A.3. Text revised 04/01/1994 I.A.4. Text revised 04/01/1994 I.A.5. Text revised 04/01/1994 VI.A. Oral Rf D referenc es revised 06/01/1995 I.A. Oral RfD noted as pending change 06/01/1995 I.A.6. Work group review date added 08/01/1995 I.A., I.A.6. EPA's RfD/RfC and CRAVEworkgroups were di scontinued in May, 1995. Chemical substance reviews that were not completed by September 1995 were taken out of IRIS review. Th e IRIS Pilot 

### http://www.epa.gov/iris/subst/0373.htmIRIS Home Chronic HealthHazards for NonCarcinogenic Effects Reference Dose for Chronic Oral Exposure (RfD)
• Oral RfD Summary • Principal and Supporting Studies • Uncertainty and Modifying Factors • Additional Studies/Comments • Confidence in the Oral RfD • EPA Documentation and Review

Reference Concentration for Program replaced the workgroup fu nctions beginning in September, 1995. 11/01/1995 I.A. Oral RfD assessment replaced 11/01/1995 VI.A. Oral RfD assessment replaced 05/01/1996 I.A.7. Secondary contact's phone number changed 12/01/1996 II.D.3. Primary contact removed 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 12/03/2002 I.A.6., I.B.6., II.D.2. Screening-Level Literature Review Findings message has been added.



### _VIII. Synonyms
Substance Name — Manganese CASRN — 7439-96-5 Last Revised — 09/26/1988

• 7439-96-5 • COLLOIDAL MANGANESE • MAGNACAT • MANGAN • Manganese • MANGAN NITRIDOVANY • TRONAMANG 

### http://www.epa.gov/iris/subst/0373.htmChronic Inhalation Exposure (RfC)
• Inhalation RfC Summary • Principal and Supporting Studies • Uncertainty and Modifying Factors • Additional Studies/Comments • Confidence in the Inhalation RfC • EPA Documentation and Review Carcinogenicity Assessment for Lifetime Exposure Evidence for Human Carcinogenicity• Weight-ofEvidence Characterization • Human Carcinogenicity Data • Animal Carcinogenicity Data • Supporting Data for Carcinogenicity Quantitative Estimate of Carcinogenic Risk from Oral Exposure

• Summary of Risk Estimates • Dose-Response Data • Additional Comments • Discussion of Confidence Quantitative Estimate of Carcinogenic Risk

from Inhalation Exposure • Summary of Risk Estimates • Dose-Response Data • Additional Comments • Discussion of Confidence • EPA Documentation, 

### http://www.epa.gov/iris/subst/0373.htmReview and, Contacts Bibliography Revision History Synonyms 

### http://www.epa.gov/iris/subst/0373.htm