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Reference Dose for Chronic Oral Exposure( RfD ) 

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Note: A Support Document for Methylmercury can be found on EPA's Office of Water Web site. The Summary and Response to the Peer Review for Methylmercury is also available in Adobe PDF format (23 Pages, 63 Kbytes). Similar documents can be found in the List of Available IRIS Toxicological Reviews.

0073 Methylmercury (MeHg); CASRN 22967-92-6

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 Methylmercury File First On-Line 01/31/1987

Oral RfD Assessment (I.A.) on-line 07/27/2001 Inhalation RfC Assessme nt (I.B.) no data 07/27/2001 Carcinogenicity Assessm ent (II.) on-line 05/01/1995 

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

## Integrated Risk Information System http://www.epa.gov/iris/subst/0073.htm Last updated on Thursday, August 09, 2012 

### http://www.epa.gov/iris/subst/0073.htmCritical Effect Expe rimental Doses* _ I.A. Reference Dose for Ch ronic Oral Exposure (RfD ) Substance Name — Methylmercury (MeHg) CASRN — 22967-92-6 Last Revised — 07/27/2001 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 or der of magnitude) of a daily exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk 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. __I.A.1. Oral RfD Summary UF MF RfD

Developmental neuropsychological impairment Human epidemiological studies (Grandjean et al., 1997; Budtz-Jørgensen et al., 1999a) Benchmark Dose: BMDL 05 range of 46-79 ppb in maternal blood for different neuropsychological effects in the offspring at 7 years of age, corresponding to a range of maternal daily intakes of 0.857-1.472 μg/kg-day 10 1 1E-4 mg/kg-day

(0.0001 mg/kg-day)

*Conversion Factors and Assumptions —Maternal daily dietary intake levels were used as the dose surrogate for the observed developmental effects in the children exposed in utero. The daily dietary intake levels were calculated from blood concentrations measured in the mothers with supporting a dditional values based on their hair concentrations. This conversion is explained in the text below. A benchmark doseapproach (BMD) was used rather than a no-observed-adverseeffect level/lowest-observed-ad verse-effect level (NOAEL/LOAEL) approach to analyze the neurological effects in children as the response variable. This analysis is also explained in the text below. This assessment updates the 1995 RfD assessment on IRIS and is the same as the RfD that was based on the study of a poisoning episode in Iraq in which developmental neurotoxicity was observed following ingestio n of methylmercury-t reated grain (Marsh et al., 1987). __I.A.2. Principal and Supporting Studies (Oral RfD) Congress directed EPA, through the House Appropri ations Report for Fiscal Year 1999, to contract with the National Research Council (NRC), a bo dy of the National Academy of Sciences, to evaluate the available data on the health effects of methylmercury, with particular emphasis on new data since the publication of the Mercury Study Report to Congress (MSRC) (U.S. EPA, 1997). NRC was asked to provide reco mmendations regarding issues relevant to the derivation of an appropriate RfD for methylmercury. The NRC re port, "Toxicological Effe cts of Methylmercury," was released to the public on July 11, 2000 (NRC , 2000). This assessment reported here relied on the quantitative analyses performed by the NRC, as described in that report. 

### http://www.epa.gov/iris/subst/0073.htmMethylmercury is a highly toxic substance; a numb er of adverse health ef fects associated with exposure to it have been identified in humans an d in animal studies. Most extensive are the data on neurotoxicity, particularly in developing orga nisms. The nervous system is considered to be the most sensitive target organ for which there are data suitable for derivation of an RfD. There are three epidemiological studies for which quantitative analyses have become available since EPA's derivation of an RfD in 1995 (NRC, 2000). These longitudinal, developmental studies were conducted in the Seychelles Islands, the Fa roe Islands, and New Zeal and. The subjects of the Seychelles longitudinal prospective study were 779 mother-infant pairs from a fish-eating population (Myers et al., 1995a-c, 1997; Davids on et al., 1995, 1998). Infants were followed from birth to 5.5 years of age, and assessed at vari ous ages on a number of standardized neuropsychological endpoints. The independent variable was ma ternal-hair mercury levels. The Faroe Islands study was a longitudinal study of about 900 mother-infant pairs (Grandjean et al., 1997). The main independent variable was cord-b lood mercury; maternal-hair mercury was also measured. At 7 years of age, children were test ed on a variety of tasks designed to assess function in specific behavioral domains. The New Zealand study was a prospective study in which 38 children of mothers with hair mercury levelsduring pregnancy greater than 6 ppm were matched with children wh ose mothers had lower hair mercury levels (Kjellstrom et al., 1989, 1986). At 6 years of age, a total of 237 ch ildren were assessed on a number of neuropsychological endpoints sim ilar to those used in the Seychelles study (Kjellstrom et al., 1989). The Seychelles study yielde d scant evidence of impair ment related to in utero methylmercury exposure, whereas the other two studies found dose -related effects on a number of neuropsychological en dpoints. In the assessment described here, emphasis is placed on the results of the Faroe Islands study, the larger of the two studies that id entified methylmercuryrelated developmental neurotoxicity. Supporting evidence from the New Zealand study provides assurance that choosing this focus is the approp riate strategy for protec ting public health. In addition, of all three studies an integrative analys is is set out later in this assessment report. EPA chose BMD analysis as the most appropri ate method of quantifying the dose-effect relationship in these studies, which was also the recommendation of the NRC (2000). EPA chose the K power model for BMD analysis , with the constraint that K >= 1, such that the model precludes supralinearity. There is no identified mechanism by which methylmercury would produce a supralinear response; therefore the K power model was thought to have more biological plausibility compared with other models. A power of 1 provided the best fit of the Faroese data using the K power model (Budtz-Jør gensen et al., 1999b, 2000), so this model was used in this RfD derivation. A value of P 0= 0.05 was used: that is, the cutoff for abnormal response was set atthe lowest 5% (5 th percentile) of children. Mo st human characteristics, including children's neurodevelopmental abilities, have an approximately bell-shaped or "normal" distribution. Generally speaking, children who function at or below approximately the 5 th percentile are considered significantly developmen tally compromised for the ability that is being measured (e.g., IQ < 75, or comparable standard scores for more specific abilities such as attention, language, or memory). A BMR of 0. 05 was chosen for this assessment, which would result in a doubling of the number of children with a response at the 5 th percentile of the population. This choice was particularly appropriat e, because effects were identified on a number of neuropsychological endpoints in the offspring at approximatel y the same body burden in the mother. A benchmark dose lower limit (BMDL 05 ) (the lower 95% confidence limit of the BMD 05 ) was calculated for each endpoint described above fr om the three studies.

DOSE CONVERSION 

### http://www.epa.gov/iris/subst/0073.htmThe biomarker of choice for the Faroese data was cord blood, an d the BMDLs were reported in units of ppb mercury in cord blood. In order to calc ulate an RfD, it is ne cessary to convert this figure to an ingested daily amount that would result in exposure to the developing fetus at the BMDL level in terms of ppb merc ury in blood. EPA chose the on e-compartment model for dose conversion for this RfD. This model has shown re asonably good fit to data on mercury blood-level changes in human subjects duri ng and after consumption of me thylmercury-contaminated fish (Ginsberg and Toal, 2000). The model is described by the formula below: d= (c x b x V)/(A x f x bw) μg/kg/day

where

• d = daily dietary intake (expre ssed as μg of methylmercury)

• c= concentration in blood (expressed as μg/L)

• b = elimination constant (expressed as days -1 )

• V= volume of blood in the body (expressed as liters)

• A= absorption factor (expressed as a unitless decimal fraction)

• f = fraction of absorbed dose taken up by blood (unitless)

• bw= body weight (expressed in kg) In this one-compartment model, all maternal compartments are compressed to one: namely, blood. It is assumed that the blood methylmercury concentration is at steady state. Concentration in blood (c)

The concentration in blood corresponds to the BMDL 05 . Fraction of mercury in diet that is absorbed (A)

After administration of radiolabel ed methylmercuric nitrate in water to three healthy volunteers, uptake was reported to be >95 % (Aberg et al ., 1969). This value is su pported by experiments involving human volunteers conduc ted by Miettinen et al. (1971). It is gene rally believed that absorption of ingested methylmerc ury is high and not likely to vary a great deal. An absorption factor of 0.95 was used as in the Mercury Study Report to Congress (U.S. EPA, 1997).

Fraction of the absorbed dose th at is found in the blood (f) Currently, four published reports address th e fraction of absorbed methylmercury dose distributed to blood volume in humans. Kershaw et al. (1980) repo rted an average fraction of 5.9% of absorbed dose in total blood volume, ba sed on a study of five adult male subjects who ingested methylmercury-contaminated tuna. In a group of nine male and six female volunteers who had received 203 Hg-methylmercury in fish, approximately 10% of the total mercury body burden was present in 1 L of blood in the first few days after exposure; this amount dropped to approximately 5% over the firs t 100 days (Miettinen et al., 1971). In another study, an average value of 1.14% for the percentage of absorbed do se per kg of blood was derived from data on subjects who consumed a known amount of me thylmercury in fish over a 3-month period (Sherlock et al., 1984). Average daily intake in the study rang ed from 43 to 233 μg/day, and there was a dose-related effect on percentage of absorbed dose that ranged from 1.03% to 1.26% in 1 L of blood. Smith et al. (1994) admi nistered radiolabeled methylmercury to seven 

### http://www.epa.gov/iris/subst/0073.htmsubjects. The paper presented published modele d data rather than observations; the mean fraction of absorbed dose in blood was 7.7% (SD, 0.88%). Stern (1997) noted that although the Smith et al. (1994) and Ke rshaw et al. (1980) data could be fit by a log-normal distribution, the data setswere too small for a reas onable determination of the underlying distributions. Stern used the mean and standard deviation of those two data sets for average parameter values as inputs to the lo g-normal distribution; th e average of the means is 0.067. Swartout and Ri ce (2000) used the observations published by Kershaw et al. (1980), Miettinen et al. (1971), and Sherlo ck et al. (1984) as adjusted fo r 5 L of blood as inputs with a log-triangular distribution. The median value was 5.9% or 0.059, close to the values of 0.05 used in the MSRC and by other groups (e.g ., Berglund et al., 1971; WHO, 1990).

EPA chose to use the median valu e of 0.059 published by Swartoutand Rice (2000) for f in the dose conversion. Elimination constant (b) Currently, five studies report clearance half-times for methylmercury from blood or hair: Miettinen et al. (1971), Kersha w et al. (1980), Al-Shahristani et al. (1974), Sh erlock et al. (1984), and Smith et al. (1994). The clearance ha lf-lives for blood in these reports are quite variable, ranging from 32 to 189 days. In the Al -Shahristani et al. (1974) study, 10% of the sample population had mercury half-lives of 110 to 120 days. Average mercury half-lives as gleaned from the five publications are 45 to70 days. The MSRC (U.S. EPA, 1997) used an average elimination constant from four of the st udies (data from Smith et al. [1994] were not used). The corresponding elimination constant of 0.014 days -1 also was noted to be the average of individual values reported for 20 volunteers in gesting from 42 to 233 μg mercury/day in fish for 3 months (Sherlock et al., 1982). Swartout and Rice (2000) applied a log-triangular distribution to the data from the five extant studies. They noted that the di stribution was highly skewed an d that the median was 53 days; the corresponding elimination constant was 0.013 days -1

. Stern (1997) discussed the variability in the data sets. His analysis of variance indicated significant differences among the sets, which were eliminated when the Al-Shahristani data were removed. The author observed that the half-livesreported by Al-Shahristani were larger than those observed in the other studie s. Stern offers the opinion that this difference may result from relatively large size of the Al-Shahristani data set as compared with the others. Stern says that an alternative explanatio n is that the Al-Shahristani data reflect a genetic polymorphism in the metabolism occurring with higher frequency in the Iraqi population, which was the subject of this study. In his ana lyses, Stern (1997) treated the Al-Shahris tani data both separately and in combination with the data from the other four st udies. He reported a mean elimination constant of 0.011 days -1 for the Al-Shahristani data alone; the combined data set mean elimination constant was 0.014 days -1

. The decision to selectpoint estimates for dose conversi on parameters was done in this assessment with the acknowledgment that some of the variability around these parameters would be truncated. This loss was compensated for by using a pharmacokine tic uncertainty factor. Nevertheless, it did not seem prudent to selecta point estimate, which is meant to reflect a population's central tendency, from one data se t only. The two central tendency estimates of Swartout and Rice (2000) and Stern (1997) were very close in value (0.013 versus 0.014); the 

### http://www.epa.gov/iris/subst/0073.htmdifferences presumably resulted from the application of different distribution types. In this assessment the value of 0.014 days -1 was used for bin the dose conversion. Volume of blood in the body (V) Stern (1997) cited three studies (Bro wn et al., 1962; Retzlaff et al., 1969; Huff and Feller, 1956) wherein correlation of body weight and blood volu me were demonstrated. All studies were of U.S. women, presumably not pregnant at the time of the study. The mean blood volumes for each study were 3.58 L, 3.76 L, and 3.49 L, respectively; the mean of the combined data set is 3.61 L. If one assumes a 30% increase in blood volume with pregnancy, this would be 4.67 L. In their analysis, Swartout and Rice (2000) used data from a cohort of 20 pregnant Nigerian women (Harrison, 1966). Whole-blood volume s in the third trimester ranged from 4 to 6 L; the mean and median were both 5 L. Although 5 L is somewhat higher th an the blood volume estimated from three studies of U.S. women, it is a reasonable value to use for V

. Body weight (bw) Swartout and Rice (2000) in their distributional analysisused the body weightdata collected on the cohort of 20 pregnant Nigerian women (Harri son, 1966); this was the da ta set that they used for blood volume. Body weight during the third trimester of pregnancy ranged from 49.5 kg to 73.9 kg, with a geometric mean of 55 kg. Ster n (1997) used the Third National Health and Nutritional Survey (NHANES III) data for wo men 18 to 40 years old (NCHS, 1995). The mean weight was 66.6 kg and the 50th percentile valu e was 62.8 kg. The EPA Me thodology for Deriving Ambient Water Quality Criteria for the Protection of Human Health (U.S. EPA, 2000) also cites NHANES III data; in the agency document, women of childbearing age were considered to be between the ages of 15 and 44 years old. The medi an body weight in this group was 63.2 kg and the mean was 67.3 kg. EPA also cites the earlier analyses of Ershow and Canter (1989); they do not state the age range but g ive a median of 64.4 kg and a mean of 65.8 kg. The recommendation in the EPA Methodology was to use a body weight value of 67 kg for a pregnant woman on the basis of the relative ly current data from NHANES III. This value was used for body weight in the dose conversion. Dose conversion using the one-compartment model d= (c x b x V)/(A x f x bw) d= (BMDL 05 μg/L x 0.014days -1 x 5L)/(0.95 x 0.059 x 67 kg)

BMD ANALYSIS OF THE FAROE ISLANDS STUDY The Faroe cohort was exposed to polychlorinated biphenyls (PCBs) as well as to methylmercury. An association was identified be tween PCB levels in cord tissue and four measures for which an effect of methylmercury also was identified (Grandjean et al., 1997). Analyses performed by the Faroe investigators indicate thatthe effects of methylmercury an d PCBs are independent of each other (Budtz-Jørgensen et al ., 1999a). Further, NRC presented an analysis of benchmark analyses designed to explore the influence of PCBs (Table 1). PCB measurements were made on cord tissue taken from about on e-half of the Faroese cohort(about 450 children) and the "adjusted for PCBs" values are based on those chil dren for whom PCB cord tissue levels and cordblood mercury levels were availabl e. PCB-adjusted analys es also were conduc ted of children in the lowest tertile with respect to PCB levels, wh ich reduced the number of children studied to about 150. No clear pattern arose from a compar ison of the PCB-adjust ed analyses and the 

### http://www.epa.gov/iris/subst/0073.htmoriginal results. The observed variability probably was no more than that which would be expected to exist by chan ce alone. This analysis provides comp elling evidence th at the effects of methylmercury identified in this study are not the consequence of exposure to PCBs.

BMD ANALYSIS OF ALL THR EE EPIDEMIOLOGICAL STUDIES Benchmark dose analyseswere performed for a number of endpoints from all three studies (Faroe Islands, Seyche lles, New Zealand) (NRC, 2000, Chap ter 7). NRC estimated a central tendency measure, equivalent to a BMD, across all three studies for all endpoints that were identified as significant in the Faroe Islands and New Zealand studies, and for all endpoints at 5.5 years of age in the Seychelles st udy. They also determined a lower limit based on a theoretical distribution of BMDs, which is the logical equivalent of a BMDL.

NRC also used a hierarchical random-effect model to reduce random variation in the estimate for these same endpoints from all three studies (NRC, 2000, Table 7-5, pp. 290-294). Additionally, this analysis was used in calc ulating BMD and BMDLs for the mostsensitive and median endpoints from both the Faroe Islands and New Zealand studies (NRC, 2000, Tabl e 7-6, p. 294). This approach also allowed an integrative anal ysis of data from all three studies. Table 1. BMD (BMDL) Estimates from the Faroe Islands Study with and without Adjustment for PCBs and in the Subset of Children Whose PCB Exposure Was Low (calculated using the K-power model)

Exposure Endpoint a Full Cohort Adjusted for PCBs Low-PCB Tertile

BMD 05 (BMDL 05 ) b BMD 05 (BMDL 05 ) BMD 05 (BMDL 05 )

Maternalhair (ppm) Finger tapping 20 (12) 17 (9) 7 (4)

CPT reaction time 18 (10) 27 (11) 13 (5) BNT 15 (10) 24 (10) 21 (6) CVLT: delayed recall 27 (14) 39 (12) 32 (7)

Cord blood (ppb) Finger tapping 140 (79) 149 (66) 41 (24)

CPT reaction time 72 (46) 83 (49) 53 (28) BNT 85 (58) 184 (71) 127 (40) CVLT: delayed recall 246 (103) 224 (78) 393 (52)

a CPT = Continuous Performance Test; BNT = Boston Naming Test; CVLT = California Verbal Learning Test. 

### http://www.epa.gov/iris/subst/0073.htmb BMDs are calculated under the assumption that 5% of the re sponses will be abnormal in unexposed subjects (P 0 = 0.05), assuming a doubling of the excess risk (BMR = 0.05). Source: E. Budtz-Jørgensen, Cope nhagen University, N. Keiding, Copenhagen University, and P. Grandjean,University of Southern Denmark, unpublis hed material, April 28, 2000, in Table 7-4, p. 289, NRC 2000. Table 2 presents BMDL 05 s from a number of endpoints in terms of cord-blood mercury. These tests are all indications of neuropsychological proc esses involved in a child's ability to learn and process information. The BMDLs for these scores are all within a relatively close range. They were converted using a one-compartment model to an ingested dose of meth ylmercury that would result in the cord-blood level. The last column shows the corresponding RfD from application of a UF of 10 (see next section). The calculated RfD values converge at the same point: 0.1 μg/kg/day. Among the endpoints from the Faroe Islands study were three deviations from 0.1 μg/kg/day: 0.2 μg/kg/day for the CVLT entire cohort and 0.05 μg/kg/day for CPT and Finger Tapping, the lowest PCB tertile. EPA also calcul ated geometric means from the four endpoints from the Faroe Islands study; RfDs were 0.1 μg /kg/day based on these calculations. For the New Zealand study smoothed values, both the median value and the results of the McCarthy Perceived Performance test yielded RfDs of 0.05 μg/kg/day, and the McCarthy Motor Test yields an RfD of 0.1 μg/kg/day. Based on the integrative analysisof all three studies, the RfD would be 0.1 μg/kg/day Table 2. Comparison of BMDL 05 s and Corresponding RfDs from Faroes, New Zealand, and NRC Integrative Analysis a

Test b BMDL 05 ppb mercury cord Ingested dose μg;/kg/day c RfD μg/kg/day d

BNT Faroes Whole cohort 58 1.081 0.1 PCB-adjusted 71 1.323 0.1 Lowest PCB 40 0.745 0.1 CPT Faroes Whole cohort 46 0.857 0.1 PCB-adjusted 49 0.913 0.1 Lowest PCB 28 0.522 0.05 CVLT Faroes Whole cohort 103 1.920 0.2 PCB-adjusted 78 1.454 0.1 Lowest PCB 52 0.969 0.1 Finger Tap Faroes Whole cohort 79 1.472 0.1 PCB-adjusted 66 1.230 0.1 

### http://www.epa.gov/iris/subst/0073.htmLowest PCB 2 4 0.447 0.0 5 Geometric mean Faroes Whole cohort 68 1.268 0.1 PCB-adjusted 65 1.212 0.1 Lowest PCB 34 0.634 0.1 Smoothed values BNT Faroes 48 0.895 0.1 CPT Faroes 48 0.895 0.1 CVLT Faroes 60 1.118 0.1 Finger Tap Faroes 52 0.969 0.1 MCCPP New Zealand 28 0.522 0.05 MCMT New Zealand 32 0.596 0.1 Median values Faroes 48 0.895 0.1 New Zealand 24 0.447 0.05 Integrative All endpoints 32 0.596 0.1

a BMDL 05 s from NRC (2000), Tables 7-4, 7-5, 7-6. Ha ir mercury was converted to blood mercury using a250:1 ratio (WHO, 1990) and an assumption of equivalent maternal and cord levels. b BNT = Boston Naming Test; CPT = Continuous Performance Test; CVLT = California Verbal Learning Test;MCCPP = McCarthy Perceived Performance; MCMT = McCarthy Motor Test.

cCalculated using a one-compartment model. d Calculated using an UF of 10. Rather than choose a single measure for the Rf D critical endpoint, EPA based this RfD for thisassessment on several scores from the Faroesmeasures, with supporting analyses from the New Zealandstudy, and th e integrative analysis of all three studies. __I.A.3. Uncertainty and Mo difying Factors (Oral RfD)

UF = 10.

MF = 1. In its report, NRC presented an analysis of the interindividual variability in the ingested dose of methylmercury corresponding to a given maternal -blood or hair-mercury concentration (NRC, 2000, pp.83-95). NRC cited two analys es of the variability and uncertainty in the ingested dose estimates based on the one-comp artment model (Stern, 1997; Swartout and Rice, 2000) as well as similar analysis of a PBPKmo del (Clewell et al., 1999). In gene ral, all three analyses found similar ranges of variability due to pharmacokine tic factors. The ratios of estimated ingested 

### http://www.epa.gov/iris/subst/0073.htmdoses at the 50 th percentile/99 th percentile ranged from 1.7 to 3.3. Using maternal blood as the starting point, the consolidated range from the three analyses is 1.7 to 3.0. Investigators have found that the placenta is not a barrier to the transfer of methylmercury from the mother to the developing fetus. Typically, a strong correlation exists between maternal-blood mercury concentrations and fetal-blood mercury concentrations, as shown by cord-blood. A review of the literature identifi ed 21 studies that reported cord -blood mercury and maternal blood mercury data (Amin-Zaki et al., 1974; Baglan et al., 1974; Dennis and Fehr , 1975; Pitkin et al., 1976; Kuhnert et al., 1981; Nishima et al., 1977; Lauwerys et al., 1978; Fujita and Takabatake, 1977; Kuntz et al., 1982; Tsuchiya et al., 1984; Truska et al ., 1989; Sikorski et al., 1989; Hansen et al., 1990; Soong et al.,1991; Soria etal., 1992; Ong et al., 1993; Akagi et al., 1997; Yang et al., 1997; Ramirez et al., 2000; Bje rregaard and Hansen, 2000; Vahter et al., 2000). Overall, data from these studies indicate that cord-blood mercury is higher than maternal blood mercury. The composite ratio from the studies re porting methylmercury concentrations indicates that the cord-blood: maternal blood ratio is around 1.7. These values are ratios of means and do not reflect the full range of variab ility in the individual mother-fet al pairs. Vahter et al. (2000) reported the 5 th and 95 th percentiles of cord:maternal Hg to be 0.88 and 3.1. Individual data were available from Fuji ta and Takabatake (1997); ratios calculated from these data ranged from 0.78 to 4.36. EPA has chosen not to make a numerical adjust ment between cord-blood and maternal-blood mercury. At this time the relationship betw een cord-blood and maternal-blood mercury is considered subject to variability and uncertainty, and is to be included in the determination of the uncertainty factor (UF).

CHOICE OF UNCERTAINTY FACTOR An RfD is based on human data, so an interspecies UF was not needed. The points of departure were the BMDL for a number of endpoints from th e Faroe Islands study, wi th supporting analyses from the New Zealand study, and an integrative analysis of all three recent large epidemiological studies. RfDs derived from these BMDLs all co nverged on the same value; this convergence provides reassurance that addition al UFs, other than for intraspeci es variability, are not needed. Further, no issues were identified that indicated the need for a modifying factor (i.e., MF = 1). The two major phenomena included in the intraspe cies UF for methylmercurywere interindividual toxicokinetic variability in ingested dose estimation and pharmacodynamic variability and uncertainty. For the former, EPA relied in part on the NRC analyses of variability in the pharmacokinetic factors un derlying the conversion of a biomar ker level of methylmercury to an ingested daily dose of methylmercury that corresp onds to that level. EPA chose not to make a numerical adjustment in the dose conversion for the potential differences between cord- and maternal-blood mercury levels, but rather tocons ider them additional as pects of toxicokinetic variability and uncertainty. A quantitative uncertainty analysis of toxicody namics was not possible. Ho wever, the population of the Faroe Islands is descended from Scandina vian stock that settled many generations ago, and is extremely homogeneous. The average to xicodynamic response of this population compared with that of the United States, which is genetically much more diverse, is unknown. Similarly, the relative variability of different populations also is unknown. A threefold UF for toxicodynamic variability and uncertainty was applied. In calculating the methylmercury RfD for this a ssessment, a composite UF of 10 was used. This choice was made to accoun t for the following factors: 

### http://www.epa.gov/iris/subst/0073.htm1

. Pharmacokinetic variability and uncertainty in estimating an ingested mercury dose from cord-blood mercury concentratio n: a factor of 3 was applied. 2. Pharmacodynamic variability and unce rtainty: a factor of 3 was applied. Choosing an overall UF of 10 is supporte d by additional anal yses of the Faroese neuropsychological data, wherein the observationsmade of the most hi ghly exposed subgroup were excluded from the model (Grandjean et al ., 1997). Associations rema ined significant when the part of the cohort with maternal-hair mercury concentrat ions greater than 10 ppm was excluded from the analyses. This finding indicates that it would be reasonable to expect some percentage of the population to show effects at or below 10 ppm hair mercury, or at levels at or below 40 ppb cord-blood. It is also important to note that no evidenceof a threshold arose for methylmercury-related neurotoxicity within the range of exposures in the Faroe Islands study. This lack is indicated by the fact that, of the K power models, K = 1 provided a better fit for the endpoint models than did highervalues of K.

ADDITIONAL IDENTIFIED DATA GAPS Areas were identified that require ad ditional research and/or analysis.

Cardiovascular effects There are two recently published studies show an association between low-level methylmercury exposure and cardiovascular effe cts. Sørensen et al. (1999) repo rted that in a study of 1,000 7-year-old Faroese children, diastolic and systol ic blood pressures increased by 13.9 and 14.6 mm Hg, respectively, as the cord-blood mercury in creased from 1 to 10 μg/L. They also reported a 47% decrease in heart rate variability (an indica tion of cardiac autonomic control) for the same increase in cord-blood mercury. Salonen et al. ( 1995) reported effects in adults from a study of 1,833 Finnish men. Over the 7-year observation period, men with hair mercury in the highest tertile (2 ppm or higher) had a 2.0 times greater ri sk of acute myocardial in farction than the rest of the study population. Persistent and delayed neurotoxicity

Another area of concern is the on set or exacerbation of neurologic al deficits in aging populations previously exposed to methylmercury. In a follow -up study of the Minamata population, Kinjo et al. (1993) reported a high preval ence of sensory disturbance in people with Minamata disease (MD). Also evaluated were "acts of daily living" (A DL) that included the abilities to independently eat, bathe, wash, dress, and use the toilet. The prevalence of deficits was relatively greater in persons with MD compared with controls as a function of increasing age. In other words, exposure to methylmercury three decades ear lier accelerated the ag ing process in aged individuals relative to younge r ones. Fukuda et al. (1999) ev aluated adults who lived in a methylmercury-polluted area near Minamata City in Japan's Kumamoto Prefecture but who were not designated MD patients; the authors then compared them with age-matched adults. Complaints that were significantly more frequent in methylmercury-contaminated areas included heart palpitation, dysesthesia, staggering when standing, restin g and intention tremor in the hands, dizziness (especially when standing), low- tone tinnitus, low-pain sensation in hands and legs, and (among women only) loss of touch sensations in hands and legs. Animal studies lend support to the conclusion that methylmercury can have delayed effects that are uncovered with age. Spyker (1975) identified neurological an d immune impairment in mice 

### http://www.epa.gov/iris/subst/0073.htmexposed prenatally to methylmercury as they approached 1 ye ar of age. Rats exposed to methylmercury in utero through 16 days of age exhi bited a decline in performance in a task that required a substantial motor output at an ea rlier age than did control rats (Newland and Rasmussen, 2000). Rice and collea gues (Rice, 1998, 1989; Rice and Hayward, 1999) identified accelerated aging of sensory system function in a series of studies in monkeys exposed during development to methylmercury. All of these observ ations are consistent wi th a hypothesis that either developmental or adult exposure to meth ylmercury can have adverse long-term sequelae that may not be detected for years or decades following cessation of exposure. However, these effects cannot be quantified based on available data. Reproductive effects Short-term, high-dose studies in rodents and guinea pigs havereported low sperm counts, testicular tubule atrophy, reduced litter size, decreased fetal survival, resorptions, and fetal malformations following exposureto methylmercury (Khera, 1973; Lee and Han, 1995; Hughes and Annau, 1976; Fuyuta et al., 1978, 1979; Hirano et al., 1986; Mitsumori et al., 1990; Inouye and Kajiwara, 1988; Suter, 1975). No studies have b een done of reproductive deficits in humans exposed to low-dose methylme rcury, nor have there been any standard, two-generation reproductive studies. Bakir et al. (1973) noted a small number of pregnant women in the Iraqi population exposed to methylmercury in trea ted grain. Burbacher et al. (1988) reported decreased conception rates, early abortions, and stillbirths in monkeys treated with methylmercury, but at higher doses than those at which behavioral deficits were identified in the offspring. Rice (1996) also found noeffect on time to pregnancy or viability of offspring at doses that produced neurotoxicity in the offspring. Th e available evidence ther efore suggests that the developing nervous system is more sensitive to methylmercury than is reproductive competence. The database upon which this RfD is based is cons idered to be of high qu ality and extensive. The effects of methylmercury on other organ systems, such as the kidney and liver, are well documented and occur at higher exposures than the effects on th e nervous system. Further, data from the most sensitive subpopulati on for nervous system effects, th e fetus, is the basis for this RfD. It is therefore considered that no additional UF(s) is warra nted at this time. However, as additional data become available, they may be used in future RfD derivation. __I.A.4. Additional Stud ies/Comments (Oral RfD) In a second Faroese cohort recruited from ch ildren born between 1994 and 1995 (Steurwald et al.,2000), decreases in neurologic optimality score (NOS) were associated with increasing cordblood mercury. This association remained statisti cally significant after ad justment for confounders (including cord and maternal serum PCB levels). There was an exposure-related decrease in NOS as cord-blood levels increased from less than 10 μg/L to greater than 40 μg/L. This finding indicates a dose-dependent effect at levelsas low as (or lower than) those for which neuropsychological deficits were reported in the study of 7-year-old children (Grandjean et al., 1997). The size of this study was relatively small (N = 182) and identified subtle changes at a very early developmental period, the clinical imp lications of which are less clear than the changes found in the study of 7-year-olds. The Marsh et al. (1987) study, chosen as the most appropriate one for determining the RfD derived by EPA for methylmercury in 1995 (U.S. EPA, 1995), reported clinical neurologic signs in 81 mother-and-child pairs. Maternal-hair mercury concentrations were the exposure metric. Concentrations ranging from 1 to 674 ppm merc ury were determined from X-ray fluorescent spectrometric analysis of selected regions of maternal scalp. Thes e were correlated with clinical signs observed in the affected members of the mother-child pairs. The hair concentration for 

### http://www.epa.gov/iris/subst/0073.htmdevelopmental effects was determined by applicat ion of a BMD approach. The analysts considered the combined incidence of all neurological effect s in children exposed in utero. A Weibull model for extra risk was used to determine the BM D; in current terminology, this was a BMDL 10(95% lower confidence limit on the dose corresponding toa 10% risk level). This level was calculated to be 11 ppm mercury in maternal-hair (11 mg/kg ha ir). The BMD of 11 ppm maternal-hair mercury was converted to an exposure le vel of 44 μg mercury/L blood usin g a 250:1 ratio as described in the MSRC (U.S. EPA, 1997, pp. 6-22-6-23). It is informative to compare RfDs derived from animal studies with those derived from the epidemiological literature. RfDs derived from mo nkey studies are particularly relevant, as the neurotoxic effects produced by developmental me thylmercury exposure in monkeys are similar to those identified in humans (Burbacher et al., 1990a; Gilbert and Grant-Webster, 1995). Studies at the University of Washington were of a relatively large cohort of macaque monkeys whose mothers were exposed throughout pregnancy to 50 μg/kg/day of methylmercury. The studies revealed deficits on cognitive tests during infancy, which may represent retarded development (Burbacher et al., 1986; Gunderson et al., 1986, 1988). These me thylmercury-exposed monkeys also displayed aberrant play and social behavi or (Burbacher et al., 1990b). Studies at the Canadian Health Protection Branch in the same species of monkey, dosed with 50 μg/kg/day from birth to 7 years of age, revealed visual, auditory, and somatosensory deficits, including evidence of delayed neurotoxicity identi fied in middle age (Rice and Gilbert, 1995, 1992, 1982; Rice, 1989). Research in a cohort of monkeys dosed beginning in uteroand continuing until 4 years of age revealed similar sensory system impairment(Rice and Hayward, 1999; Rice, 1998; Rice and Gilbert, 1995, 1990). Three individuals dosed at 10 or 25 μg/kg/day all exhibited impaired function in at least one sensory system in additi on to evidence of delayed neurotoxicity (Rice, 1998). In none of these studies wa s a NOAEL identified. Reference doses derived from these data would yield an RfD of 0.05 μg/kg/day from the in uteroand postnatal exposure studies, and an RfD as low as 0.01 μg/kg/day based on combined in uteroand postnatal exposure (Rice, 1996). The doses would be based on an UF of 10 to extrapolate from a LOAEL to a NOAEL and an UF of 10 to extrapolate from animals to humans. Gilb ert and Grant-Webster (1995) suggested an RfD of 0.025 μg/kg/day based on the same data. __I.A.5. Confidence in the Oral RfD Study — High Database — High RfD — High

The overall confidence in this RfD assessment ishigh. Three high-quality epidemiological studies have been published since the lastderivation of the oral RfD in 1995. Two of the studies (Faroe Islands, New Zealand) re ported effects on a number of ne uropsychological endpoints, whereas the third (Seychelles Islands) reported no effect s related to in utero exposure to methylmercury. Benchmark dose analysis of a number of endpoin ts from both the New Zealand and Faroe Islands study converged on an RfD of 0.1 μg/kg-day, as did the integrative analysis combining all three studies. Although there was coexpo sure to PCBs in the Faroe Islands study, statistical analysis indicated that the effects of PCBs and methyl mercury were independen t. Moreover, benchmark dose analysis of the endpoints th at were significantly associated with methylmercury yielded RfDs that were approximately the sa me when corrected for PCBs. The same was true when the analysis was or based on the subset of the cohort in the lowest tertile with respect to PCB levels, as compared with the full cohort . These findings prov ide further evidence that the identified effects are in fact the result of methylmercury exposure. 

### http://www.epa.gov/iris/subst/0073.htmThe RfD used in this asse ssment report is the same as that derived in 1995 based on a study of a poisoning episode in Iraq. Experimental studies in monkeys also support the quantitative estimate of the RfD based on a NO AEL/LOAEL approach. Thus, there isa wealth of data from both epidemiological and experimental studies that co nverges on the derived RfD of 0.1 μg/kg/day. __I.A.6. EPA Documentation and Review of the Oral RfD Source Document — U.S. EPA, 2001 All reviewers' comments have been carefully ev aluated and considered in the revision and finalization of this IRIS Summary. A record of these comments is summarized in the IRIS documentation files. To review, exit to the Summary and Response to the Peer Review for Methylmercury document (PDF)

. Other EPA Documentation — U.S. EPA, 1980, 1984, 1987, 1988, 1995 Consensus Date - 06/19/2001 Screening-Level Literature Review Findings — A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for Methylmercury conducted in September 2002 did no t identify any critical new stud ies. 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. __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 — Methylmercury (MeHg) CASRN — 22967-92-6

Not available at this time.



### _II. Carcinogenicity Asse ssment for Lifetime Exposure Substance Name — Methylmercury (MeHg) CASRN — 22967-92-6 Last Revised — 05/01/1995 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 carcinogen, 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 

### http://www.epa.gov/iris/subst/0073.htmconcentration 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. _II.A. Evidence for Human Carcinogenicity __II.A.1. Weight-of-Evid ence Characterization Classification — C; po ssible human carcinogen Basis — Based on inadequate data in humans and limited evidence of carcinogenicity in animals. Male ICR and B6C3F1 mice expo sed to methylmercuric chloride in the diet ha d an increased incidence of renal adenomas, ad enocarcinomas and carcinomas. The tumors were observed at a single site and in a single species and single se x. The renal epithelial cell hyperplasia and tumors were observed only in the presence of profou nd nephrotoxicity and were suggested to be a consequence of reparative change s in the cells. Several nonposit ive cancer bioassays were also reported. Although genoto xicity test data suggest that meth ylmercury is capable of producing chromosomal and nuclear damage, there are also nonpositive genotoxicity data. __II.A.2. Human Carcinogenicity Data Inadequate. Three studies were identified that examined the relationshipbetween methylmercury exposure and cancer. No persua sive evidence of increased carcinogenicity attributable to methylmercury exposure was observed in any of the studies. Interpretation of these studies, however, was limited by poor st udy design and incomplete descr iptions of methodology and/or results. Tamashiro et al. (1984) evaluated the causes of death in 334 subjectsfrom the Kumamoto Prefecture who had been diagnose d with Minamata disease (meth ylmercury poisoning) and died between 1970 and 1980. The subjects involved fishermen and th eir families who had been diagnosed with the disease; thus, Minamata dise ase was used as a surrogate for methylmercury exposure. The controls were select ed from all deaths that had occurred in the same city or town as the cases and were matched on the basis of se x, age at death (within 3 years) and year of death; two controls were matched to each subject. Malignant neoplasms we re designated as the underlying cause of deat h in 14.7% (49/334) of the subjects and 20.1% (134/668) of the controls. For 47 subjects in which Minamata disease was listed as the underlying cause of death, the investigators reanalyzed the mortality data an d selected one of the secondary causes to be the underlying cause of death in order to allow examination of the subjects and controls under similar conditions and parameters . The three subjects for which Minamata disease was listed as the only cause of death were excluded from further analysis. Using the Mantel-Haenzel method to estimate odds ratios, no significant differences were observed between the subjects and controls with respect to the proportion of deaths due to ma lignant neoplasms among males, females or both sexes combined. The estimated odds rati os and 95% confidence intervals were 0.84 (0.49-1.43), 0.58 (0.28-1.21) and 0.75 (0.50-1.11) for males, females and both sexes combined. Similarly, no increases in odds ratio were observ ed among the subjects relative to the controls when malignant neoplasms were identified as a se condary cause of death or were listed on death certificates as one of the multiple causes of de ath. These data suggest th at cancer incidence was not increased in persons with overt signs of methylmercury po isoning when compared with 

### http://www.epa.gov/iris/subst/0073.htmpersons for whom no diagnosis of methylmercury poisoning had been made. Interpretation is limited by potential bias in de signating the cause of death amon g patients with known Minamata disease and by the uncertainty re garding the extent of methylmercury exposure and undiagnosed Minamata disease among the controls. In a subseq uent study, Tamashiro et al. (1986) compared the mortality patterns (between 1970 and 1981) among residents of the Fukuro an d Tsukinoura districts in the Kumamoto Prefectu re (inhabited mainly by fishermen and their families) with that of age-matched residents of Mina mata City (also in the Kumamoto Prefecture) who died between 1972 and 1978. In this study, high exposure to methylmercury was inferre d from residence in a district believed to have higher intake of loca l seafood. By contrast, in the 1984 study described above, high methylmercury exposu re was inferred from a diagnosis of Minamata disease. A total of 416 deaths were recorded in the Fukuro and Tsukinoura districts in 1970-1981, and 2325 deaths were recorded in Minamata City in 1972-1978. No statistica lly significant increase in the overall cancer mortality rate was observed; howeve r, an increase in the mortality rate due to liver cancer was observed (SMR, 207.3; 95% CI , 116.0-341.9). Analysisof mortality by sex showed a statistically significan t increase in the rate of liver cancer only among males (SMR, 250.5; 95% CI, 133.4-428.4). Males also had statis tically signific ant higher mortality due to chronic liver disease and cirrhosis. The authors notethat these results should be interpreted with caution because the population of the Fukuro and Tsukinoura district s had higher alcohol consumption and a higher prevalen ce of hepatitis B (a predisposi ng factor for hepatocellular cancer). Interpretation of thes e results is also limited by an incomplete description of the methodology used to calculate the SMRs; it is unclear whether the study authors used appropriate methods to compare mortality data co llected over disparate time frames (12 years for exposed and 7 years for controls). In a study from Poland, Janicki et al. (1987) reported a statisti cally significan t increase in mercury content of hair in leukem ia patients (0.92 +/- 1.44 ppm [sic]; n=47) relative to that in healthy unrelated patients (0.49 +/- 0.41 ppm; n=79). Similarly, the mercury content in the hair of a subgroup of leukemia patients (0.69 +/- 0.75; n=19) was significantly greater than that in healthy relatives who had shared the same reside nce for at least 3 years preceding the onset of the disease (0.43 +/- 0.24 ppm; n=52). When patien ts with specific types of leukemia were compared with the healthy unrelated subjects (0 .49 +/- 0.41 ppm; n=79), only those with acute leukemia (type not specified; 1.24 +/- 1.93 pp m; n=23) had a significantly increased hair mercury content. No significant differences in hair mercury content were observed in 9 patients with chronic granulocytic leukemia or 15 pati ents with chronic lymp hocytic leukemia when compared with the unrelated, healthy controls . The authors inferred th at acute leukemia was associated with increased level of mercury in hair. This study is of limited use for cancer risk assessment because of the foll owing: uncertainty regarding the correlation between the chronology of incorporation of mercury in the hair and onset of the disease; the small population studied; the failure to describe adequately the characteristics of the leukemia patients or healthy controls (age distribution, length of residence in the region, criteria for inclusion in the study); uncertainty regarding the source of mercury expo sure (the authors presumed that exposure was the result of use of methylmercury-containing fung icides); and the failure to address exposure to other chemicals or adjust for other leukemia riskfactors. Furthermore, the variability of hair mercury content was large, and the mean hair me rcury levels were within normal limits for all groups. Thus, the statistical significance may have been due to chance. The carcinogenic effects of organomercury seed dressing exposu re were investigated in a series of case-control studies for inci dence of soft-tissue sarcomas (E riksson et al., 1981, 1990; Hardell and Eriksson, 1988) or malignant lymphoma s (Hardell et al., 1981). These studies were conducted in Swedish populations exposed to phenox yacetic acid herbicides or chlorophenols (the exposures of primary interest in the studies), organomercury seed dressings, or other pesticides. Exposure frequencies werederived from questionnaires and/or interviews. Control groups from 

### http://www.epa.gov/iris/subst/0073.htmthe same region of the country were matched to cases based on vital status. A total of 402 cases of soft-tissue sarcoma and (among persons not exposed to phenoxyacetic acid herbicides) 128 cases of malignant lymphoma were reported. In each study, the odds ratio for exposure to organomercury in seed dressings and the incidenc e of sarcoma or lymphoma was either <1.0 or the range of the 95% confidenceinterval for the odds ratio included 1.0; therefore, no association was indicated for organomercury ex posure and soft-tissue sarcoma or malignant lymphoma. The study subjects were likely to haveexperienced exposures tothe other pesticides and chemicals. __II.A.3. Animal Carcinogenicity Data Limited. Three dietary studies in two strains of mi ce indicate that methylmercury is carcinogenic. Interpretation of two of the positive studies wa s complicated by observat ion of tumors only at doses that exceeded the MTD. A fourth dietary study in mice and four dietary studies in rats failed to indicate carcinogenicity associated with methylmercury ex posure. Interpretation of four of the nonpositive studies was limited because of de ficiencies in study design or failure to achieve an MTD. Methylmercuric chloride (>99% pure) was administered in the diet at levels of 0, 0.4, 2 or 10 ppm (0, 0.03, 0.15 and 0.73 (mg/kg)/day in ma les and 0, 0.02, 0.11 and 0.6 (mg/kg)/day in females) to 60 ICR mice/sex/group for 104 week s (Hirano et al., 1986). Interim sacrifices (6/sex/group) were conducted at26, 52 and 78 weeks. Complete histopathological examinations were performed on all animals foun d dead, killed in extremis or killed by design. Mortality, group mean body weights and food consumption were comparable to controls. The first renal tumor was observed at 58 weeks in a high-dose male, and the incidence of renal epithelial tumors (adenomas or adenocarcinomas) wa s significantly increased in high-dose males (1/32, 0/25, 0/29 and 13/26 in the control, low-, mid- and high-dose groups, respectively). Ten of the 13 tumors in high-dose males were adenocarcinomas. These tumo rs were described as solid type or cystic papillary types of adenocarcinomas. No invading proliferation into the surrounding tissues was observed. The incidence of renal epithelial adenomas was not significantly increased in males, and no renal adenomas or adenocarcinomas we re observed in any females studied. Focal hyperplasia of the tubular epithelium was reported to be increased in high-dose males (13/59; other incidences not reported). Increases in non-ne oplastic lesions in high- dose animals provided evidence that an MTD was exceeded. Non-neoplast ic lesions reported as increased in treated males included the following: epithelial degeneration of the renal proximal tubules; cystic kidney; urinary cast and pelvic dilatation; and decreased sp ermatogenesis. Epithelial degeneration of the renal proximal tubules and degenera tion or fibrosis of the sciatic nerve was reported in high-dose females. Methylmercuric chloride (>99% pure) was administered in the diet at levels of 0, 0.4, 2 or 10 ppm (0, 0.3, 0.14 and 0.69 (mg/kg)/day in ma les and 0, 0.03, 0.13 an d 0.60 (mg/kg)/day in females) to 60 B6C3F1 mice/sex/group for 104 w eeks (Mitsumori et al., 1990). In high-dose males, a marked increase in mortality was obse rved after week 60 (data presented graphically; statistical analyses not performe d by authors). Survival at stud y termination was approximately 50, 60, 60 and 20% in control, low-, mid- and high-dose males, respectively, and 58, 68, 60 and 60% in control, low-, mid- and high-dose females, respectively. The cause of the high mortality was not reported. At study termination, the mean body weight in high-dose males was approximately 67% of controls and in high-dos e females was approximately 90% of controls (data presented graphically; stat istical analyses not performed by study authors). The incidence of focal hyperplasia of the renal tubules was si gnificantly increased in high-dose males (14/60; the incidence was 0/60 in all other groups). The incidence of renal epithelial carcinomas (classified as solid or cystic papillary type) was also significantly increa sed in high- dose males 

### http://www.epa.gov/iris/subst/0073.htm(13/60; the incidence was 0/60 in all other groups). The incidence of renal adenomas (classified as solid or tubular type) was also significantly increased in high-dose males; the incidence was 0/60, 0/60, 1/60 and 5/60 in cont rol, low-, mid- and high-dose males, respectively, and 0/60, 0/60, 0/60 and 1/60 in control low-, mid- and high-dose females, respectively. No metastases were seen in the animals. The inci dences of a variety of non- neoplastic lesions were increased in the high-dose mice including the following: sensory neuropathy; neuronal necrosis in the cerebrum; neuronal degeneration in the cerebellum; and chroni c nephropathy of the kidney. Males exhibited tubular atrophy of the testis (1/ 60, 5/60, 2/60 and 54/60 in control, low-, midand high-dose, respectively) and ulceration of the glandular stomach (1/60, 1/60, 0/60 and 7/60 in control, low-, mid- and high - dose males, respectively). An MTD was achieved in mid-dose males and high- dose females. High mortality in high-dose ma les indicated that the MTD was exceeded in this group. Mitsumori et al. (1981) administered 0, 15 or 30 ppm of methylmerc uric chloride (>99% pure) in the diet (0, 1.6 and 3.1 (mg/kg)/day) to 60 ICR mi ce/sex/group for 78 weeks. Interim sacrifices of up to 6/sex/group were conducted at w eeks 26 and 52. Kidneys were microscopically examined from all animals that died or became moribund after week 53 or were killed at study termination. Lungs from mice with renal masses and renal lymph nodes showing gross abnormalities were also examined. Survival was decreased in a dose- related manner; at week 78 survival was 40, 10 and 0% in control, low- and high-dose males, respectively, and 55, 30 and 0%, in control, low- and high- dose females, re spectively (statistical analyses not performed). The majority of high-dose mice (85% males and 98% females) died by w eek 26 of the study. Examination of the kidneys of mice that died or were sacr ificed after 53 weeks showed a significant increase in renal tumors in low-do se males (13/16 versus 1/37 in controls). The incidence of renal epithelial adenocarcinomas in control and low-dose males was 0/37 and 11/16, respectively. The incidence of renal epithelial adenomas in control and low-dose males was 1/37 and 5/16, respectively. No renal tumors were observed in females in any group. No metastases to the lung or renal lymph nodes were observed . Evidence of neurotoxicity and renal pathology were observed in the treated mice at both doselevels. The high mortality in both groups of treated males and in high- dose females indicated that the MTD was exceeded in these groups. (Note: Hirano et al. (1986) wa s a followup to this study.) Mitsumori et al. (1983, 1984) administered di ets containing 0, 0.4, 2 or 10 ppm of methylmercuric chloride (0, 0. 011, 0.05 and 0.28 (mg/kg)/day in males; 0, 0.014, 0.064 and 0.34 (mg/kg)/day in female s) to 56/sex/group Sprague-Dawley rats for up to 130 weeks. Interim sacrifices of 10/group (either sex) were conducted at weeks 13 and 26 and of 6/group (either sex) at weeks 52 and 78. Mortality was increased in high-dose ma les and females. At week 104, survival was approximately 55, 45, 75 and 10% in control, low-, mid- and high-dose males, respectively, and 70, 75, 75 and 30% in control, low-, mid- and high-dose females, respectively (data presented graphically). Al l males in the high-dose group had died by week 119. Body weight gain was significantly decreased in high -dose males starting af ter week 44 and females after 44 weeks (approximately 10-20%, data presented graphically). No increase in tumor incidence was observed in either males or females. Noncarcinogenic lesions that were significantly increased in high-dose rats included the following: degeneration in peripheral nerves and the spinal cord (both sexes); degeneration of the proximal tubular epithelium (both sexes); severe chronic nephropathy (females); parathyroi d hyperplasia (both sexes) ; polyarteritis nodosa and calcification of arterial wall (females); fibrosis of bone (females); bile duct hyperplasia (males); and hemosiderosis and extramedullary hematopoiesis in the spleen (males). Mid-dose males exhibited significantly in creased degeneration of the proximal tubular epithelium and hyperplasia of the parathyroid. An MTD was achi eved in mid-dose males and exceeded in highdose males and high-dose females. 

### http://www.epa.gov/iris/subst/0073.htmNo tumor data were reported in a study using Wistar rats (Munro et al., 1980). Groups of 50 Wistar rats/sex/dose were fed diets containing me thylmercury; doses of 2, 10, 50 and 250 (ug/kg)/day were fed for 26 months. High-dose fema le rats exhibited redu ced body weight gains and showed minimal clinical signs of neurotoxicity; however, high-dose male rats showed overt clinical signs of neurotoxicity, decreased hemogl obin and hematocrit values, reduced weight gains and significantly increased mortality. Histopathologic examination of the high-dose rats of both sexes revealed demyelination of dorsal nerve roots and peripheral nerves. Males showed severe dose-related kidney damage, and fe males had minimal renal damage.

No increase in tumor incidence or decrease in tumor latency was observed in another study using rats of an unspecified strain (Verschuuren et al., 1976). Groups of 25 fe male and 25 male rats were administered methylmercuric chloride at dietary levels of 0, 0.1, 0.5 and 2.5 ppm (0, 0.004, 0.02 and 0.1 (mg/kg)/day) for 2 ye ars. No significant effects wereobserved on growth or food intake except for a 6% decrease (statistically significant) in body weight gain at 60 weeks in high-dose females. Survival was 72, 68, 48 and 48% in control, low-, mid- and high-dose males, respectively, and 76, 60, 64 and 56% in control, low-, mid- and high-dose females, respectively (statistical significance not report ed). Increases in relative kidney weights were observed in both males and females at the highest dose. No effects on the nature or incidence of pathological lesions were observed, and tumors were report ed to have been observed with comparable incidence and latency among all of the groups. Th is study was limited by the small sample size.

No increase in tumor incidence was observed in a study using white Swiss mice (Schroeder and Mitchener, 1975). Groups of mice (54/sex/group) were exposed until death to methylmercuric acetate in the drinking water attwo doses. The low-dose grou p received 1 ppm methylmercuric acetate (0.19 (mg/kg)/day). The high-dose group received 5 ppm methylmercuric acetate (0.95 (mg/kg)/day) for the first 70 days and then 1 ppm thereafter, due to high mortality (21/54 males and 23/54 females died prior to the dose reduct ion). Survival among the remaining mice was not significantly different from controls. Significant re ductions in body weight were reported in highdose males (9-15% lower than controls) and hi gh-dose females (15-22% lower than controls) between 2 and 6 months of age. After dying, mice were weig hed and dissected; gross tumors were counted, and limited histop athologic sections were made of heart, lung, liver, kidney and spleen for microscopic examination. This stud y is limited because complete histological examinations werenot performed.

No increase in tumor incidence was observed in a multiple-generation reproduction study using Sprague-Dawley rats (Newberne etal., 1972). Groups of rats ( 30/sex) were give n semisynthetic diets supplemented with eith er casein or a fish protein concentrate to yield dietary levels of 0.2 ppm methylmercury (0.008 (mg/kg)/day). Anothe r group of controls re ceived untreated rat chow. Rats that received diet s containing methylmercury during the 2-year study had body weights and hematology comparable to controls. Detailed histopathological analyses revealed no lesions of the brain, liver, or kidney that wereattributable to methylmercury exposure. Mortality data were not presented. Interpretation of thes e data is limited by th e somewhat small group sizes and failure to achieve an MTD. __II.A.4. Supporting Data for Carcinogenicity Blakley (1984) administered meth ylmercuric chloride to female Swiss mice (number/group not specified) in drinking water at concentratio ns of 0, 0.2, 0.5 or 2.0 mg/L for 15 weeks (approximately 0, 0.03, 0.07 and 0. 27 (mg Hg/kg)/day). At the end of week 3, a single dose of 1.5 mg/kg of urethane was administered intrap eritoneally to 16-20 mice/group. No effects on weight gain or food consumption were observed. Lung tumor incidence in mice not administered urethane (number/group not specified) was less than one tumor/mouse in all groups. Statistically 

### http://www.epa.gov/iris/subst/0073.htmsignificant trends for increases in the number and size of lung adenomas/mouse with increasing methylmercury dose were observ ed; the number of tumors/mousewas 21.5, 19.4, 19.4 and 33.1 in control, low-, mid- and hi gh-dose mice, respectively, and the tumor size/mouse was 0.70, 0.73, 0.76 and 0.76 mm in control, low-, mid- and high-dose mice, respectively. The study authors suggest that the increa se in tumor number and size may have been related to the immunosuppressive activity of methylmercury. It should be noted that this study is considered a short-term bioassay, and pu lmonary adenomas were the only tumor type evaluated. Humans ingesting methylmercury-contaminated foods have been reported to experience chromosomal aberrations (Skerf ving et al., 1970, 1974) or SCE (Wulf et al., 1986); however, interpretation of these studies is limited by methodological deficiencies. As reviewed in WHO (1990), methylmercury is not a potent mutagen but appears to be capable of causing chromosome damage and nuclear pertur bations in a variety of systems. In Bacillus subtilis, methylmercury prod uced DNA damage (Kanematsu et al., 1980). Methylmercury produced chromosomal aberrations and aneuploidy in hu man peripheral lympho cytes (Betti et al., 1992), SCE in human lymphocyte s (Morimoto et al., 1982), and DNA damage in human nerve and lung cells as well as Chinese hamster V-79 cells and rat glioblastoma cells (Costa et al., 1991). Bone marrow cells of cats treated with methyl mercury in a study by Charbonneau et al. (1976) were examined by Miller et al . (1979). The methylmercury treatm ent resulted in an increased number of nuclear abnormalities and an inhibition of DNA repair capacity. Methylm ercury induced a weak mutagenic respon se in Chinese hamster V-79 cells (F iskesjo, 1979). Methylmercury also induced histone protein perturbations and influenced factors regulating nucleolus-organizing activity (WHO, 1990). Moreover, methylmercury has been reported to interfere with gene expression in cultures of glioma cells (WHO, 1990). Mailhes ( 1983) reported a significant increase in the number of hyperploid oocysts in Lak:LV G Syrian hamsters fed methyl mercury; however, no evidence of chromosomal damage was report ed. Suter (1975) conclude d that strain-specific differences exist with respect to the ability of methylmercury to produce dominant lethal effects in mice. Nondisjunction and sex-linked recessive lethal mutations were ob served in Drosophila melanogaster treated with methylmercury (Ramel, 1972 as cited in U.S. EPA, 1985). Methylmercury produced single strand breaks in DNA in cultured L5178Y cells (Nakazawa et al., 1975). Negative studies have also been reported. Methyl mercury acetate was reported to be negative in a Salmonella typhimurium assay and a mouse micronucleus assay (Heddle and Bruce, 1977, as reported in Jenssen and Ramel, 1980). Methyl mercury was not mutagenic and did not cause recombination in Saccharomyces cerevisiae but di d slightly increase chro mosomal nondisjunction (Nakai and Machida, 1973). Matsum oto and Spindle (1982) reported no significant increase in SCE in developing mouse embryo s; they did report , however, that the developing mouse embryos were highly sensitive to in vitro treatment with methylmercury.

_II.B. Quantitative Estimate of Carcin ogenic Risk from Oral Exposure None. The two studies by Mitsumori et al. (1981, 1990) were limited by high mortality in the high-dose males, the only group to exhibit a statistically significant increase in tumor incidence. Tumors were observed only in those dose groups in which the MTD had been exceeded. The study by Hirano et al. (1986) was not limited bylow survival, but the tumors were observed in conjunction with nephrotoxicity and, thus, their incidence may have been a high-dose phenomenon that would not be expe cted to occur at low doses. Th e tumors appeared to originate 

### http://www.epa.gov/iris/subst/0073.htmfrom focal hyperplasia of the tubular epithelium induced as a reparative change. The hyperplasia was not observed in tubular epithelium that was undergoing early degenerative changes. Thus, the tumors may not occur where degenerative ch anges do not occur. The genotoxicity data indicate that methylmercury is not a potentmutagen but may produce chromosomal damage; these data do not support a hypothesis that meth ylmercury is a genotoxic carcinogen. It appears, rather, that methylmercury exerts its carcinogenic effect only at high dose, at or above an MTD. Because the linearized multistage procedure is base d on the assumption of linearity at low doses, the relevance of deriving a slope factor based on data for which a threshold may exist is questionable. It is likely that systemic no n-cancer effects would be seen at methylmercury exposures lower than those required for tumor formation. Long - term administration of methylmercury to experimental animals produces overt symptoms of neuroto xicity at daily doses an order of magnitude lower than those required to induce tumors in mice.

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

None.

_II.D. EPA Documentation, Review, and Contacts (C arcinogenicity Assessment) __II.D.1. EPA Documentation Source Documents -- U.S. EPA, 1995 This IRIS Summary is included in The Mercury St udy Report to Congress which was reviewed by OHEA and EPA's Mercury Work Group in November 1994. An Interagency Review by scientists from other federal agencies took place in Janu ary 1995. The report was al so reviewed by a panel of non-federal external scientists in January 1995 who met in a public me eting on January 25-26. All reviewers comments have b een carefully evaluated and considered in the revision and finalization of this IRIS summary. A record of these comments is summarized in the IRIS documentation files. __II.D.2. EPA Review (Car cinogenicity Assessment) Agency Work Group Review — 03/03/1994 Verification Date — 03/03/1994 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 Methylmercury conducted in September 2002 did not id entify 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). 

### http://www.epa.gov/iris/subst/0073.htm

### _III. [reserved] _IV. [reserved] _V. [reserved] _VI. Bibliography Substance Name — Methylmercury (MeHg) CASRN — 22967-92-6 Last Revised — 07/27/2001 _VI.A. Oral RfD References Aberg, B; Ekman, L; Falk, R; et al. (1969) Metabolis m of methyl mercury (203Hg) compounds in man. Arch Environ Health 19:478-484. Akagi-H, I; Kanoka; Kaneko, K. (1997) J Jpn Soc Obstet Gynecol Neonat Hematol 7(2):S112- S113. Al-Shahristani, H; Shihab, KM. (1974) Variation of biological half- life of methyl mercury in man. Arch Environ Health 28:342-344. Amin-Zaki, L; Elhassani, S; Majeed, MA; et al. (1974) Intra-uterine methylmercury poisoning in Iraq. Pediatrics 54:587-595. Baglan RJ; Brill, AB; Schulert, A; et al. (1974) Utility of placental tissue as an indicator of trace element exposure to adult and fetus. Environ Res 8:64-70. Bakir, F; Damluji, S; Amin-Zak i, L; et al. (1973) Methylmercury poisonin g in Iraq. Science 181:230-241. Berglund, F; Berlin, M; Birke, G; et al. (1971) Methyl mercury in fish: a toxicologic- epidemiologic evaluation of risks. Report from an expert grou p. Nordisk Hygienisk Tidskrift, Stockholm Suppl. 4:19-364. Bjerregaard P; Hansen, JC. (2000) Organochlorines and heavy meta ls in pregnant women from the Disko Bay area in Greenland. Sci Total Environ 17:245(1-3):195-202. Brown, E; Hopper, J; Hodges, JL Jr; et al. (196 2) Red cell, plasma, and blood volume in healthy women measured by radiochrom ium cell-labeling and hematocr it. J Clin Invest 41:2182-2190. Budtz-Jørgensen, E; Keiding, N; Grandjean, P; et al. (1999a) Methylmercury neurotoxicity independent of PCB exposure . [Letter]. Environ Health Perspect 107(5):A236-237. Budtz-Jørgensen, E; Keiding, N; Grandjean, P. (1999b) Benchma rk modeling of the Faroese methylmercury data. Final Report toU.S. EPA. Research Report 99/5. Department of Biostatistics, University of Copenhagen. Budtz-Jørgensen, E; Grandjean, P; Keiding, N; et al. (2000) Benchmark dose calculations of methylmercury-associated neurobehavio ral deficits. Toxicol Lett 112-113:193-199. 

### http://www.epa.gov/iris/subst/0073.htmBurbacher, TM; Grant, KS; Mott et, NK. (1986). Retarded objectpermanence development in methylmercury exposed Macaca fascicular is infants. Dev Psychobiol 22:771-776. Burbacher, TM; Mohamed, MK; Mo ttett, NK. (1988) Methyl mercury effects on reproduction and offspring size at birth. Reprod Toxicol 1:267-278. Burbacher, TM; Rodier, PM; Wei ss, B. (1990a) Methylmercury de velopmental neurotoxicity: a comparison of the effects in humans and animals. Neurotoxicol Teratol 12:191-202. Burbacher, TM; Sackett, GP; Mott et, NK. (1990b) Methylme rcury effects on the social behavior of Macaca fascicularis infants. Neurotoxicol Teratol 12:65-71. Clewell, HJ; Gearhart, JM; Gentry, PR; et al. ( 1999) Evaluation of the un certainty in an oral reference dose for methylmercury du e to interindividual variability in pharmacokinetics. Risk Anal 19:547-558. Davidson, P; Myers, G; Cox, C; et al. (1995) Longitudinal neurodevelopmental study of Seychellois children following in utero exposure to methylmercury from maternal fish ingestion: outcomes at 19 and 29 months . NeuroToxicology 16:677-688. Davidson, PW; Myers, GJ; Cox, C; et al. (1998) Effects of prenatal and postnatal methylmercury exposure from fish co nsumption on neurodevelopment: outcomes at 66 months of age in the Seychelles child developmen t study. JAMA 280:701-707. Dennis, CA; Fehr F. (1975) The re lationship between mercury levels in maternal and cord-blood. Sci Total Environ 3(3):275-277. Ershow, AG; Canter, KP. (1989) Total water and tapw ater intake in the Unit ed States: populationbased estimates of quantities and sources. Life Sciences Research Office, Federation of American Societies for Experimental Biology, Bethe sda, MD. (Prepared under NCI #263-MD-810264.) Fujita, M; Takabatake, E. (1977) Mercury levels in human maternal and neonatal blood, hair and milk. Bull Environ Contam Toxicol 18(2):205-209. Fukuda, Y; Ushijima, K; Kitano, T. (1999) An ana lysis of subjective comp laints in a population living in a methylmercury-pollu ted area. Environ Res 81:100-107. Fuyuta, M; Fujimoto, T; Hirata, S. (1978) Embryotoxic effe cts of methylmercuric chloride administered to mice and rats during organogenesis. Tera tology 18(3):353-366. Fuyuta, M; Fujimoto, T; Ki yofuji, E. (1979) Teratogenic effects of a single oral administration of methylmercuric chloride in mice. Acta Anat (Basel) 104(3):356-362. Gilbert, SG; Grant-Webster, KS. (1995) Neurobeh avioral effects of deve lopmental methylmercury exposure. Environ Health Pe rspect 103 Suppl. 6:135-142. Ginsberg, GL; Toal, BF. (2000) Development of a single-meal fish consumption advisory for methylmercury. Risk Anal 20:41-47. Grandjean, P; Weihe, P; White, R; et al. (199 7) Cognitive deficit in 7-year-old children with prenatal exposure to methylmercury. Neurotoxicol Teratol 20:1-12. 

### http://www.epa.gov/iris/subst/0073.htmGunderson, VM; Grant, KS; Fagan, JF. (1986) Th e effect of low-level prenatal methylmercury exposure on visual re cognition memory of infant crab-e ating macaques. Child Dev 57:1076-1083. Gunderson, VM; Grant-Webster, KS; Burbacher, TM; et al. (1988) Visual recognition memory deficits in methylmercu ry-exposed Macaca fasci cularis infants. Neurot oxicol Teratol 10:373-379. Hansen, JE; Tarp, U; Bohm, J. (1990) Prenatal exposure to methyl mercury among Greenlandic Polar Inuits. Arch Environ Health 45:355-358. Harrison, KA. (1966) Blood volume changes in norm al pregnant Nigerian women. J Obstet Gynaec Br Cwlth 73:717-723. Hirano, M; Mitsumori, K; Maita, K; et al. (1986). Further carcin ogenicity study on methylmercury chloride in ICR mice. Nipon Juigaku Zasshi (Jpn J Vet Sci) 48(1):127-135. Huff, RL; Feller, DD. (1956) Relation of circulatin g red cell volume to body density and obesity. J Clin Invest 35:1-10. Hughes, JA; Annau, Z. (1976) Post natal behavioral effects in miceafter prenatal exposure to methylmercury. Pharmacol Biochem Behav 4(4):385-391. Inouye, M; Kajiwara, Y. (1988). Developmental disturbances of the fetal brain in guinea pigs caused by methylmercury. Arch Toxicol 62(1):15-21. Kershaw, TG; Clarkson, TW; Dhahir, PH. (1980) Th e relationship between blood levels and the dose of methylmercury in man. Arch Environ Health 35(1):28-36. Khera, KS. (1973) Reproductive capability of male rats and mi ce treated with methylmercury. Toxicol Appl Pharmacol 24(2):167-177. Kinjo, Y; Higashi, H; Nakano, A; et al. (1993) Profile of subjective comp laints and activities of daily living among current patients with Minamata disease after 3 decades. Environ Res 63 (2):241-251. Kjellstrom, T; Kennedy, P; Wallis, S; et al. ( 1986) Physical and mental development of children with prenatal exposure to mercury from fish. St age 1: Preliminary test at age 4. Natl Swed Environ Protec Bd, Rpt 3080 (Solna, Sweden). Kjellstrom, T; Kennedy, P; Wallis, S; et al. ( 1989) Physical and mental development of children with prenatal exposure to mercury from fish. St age 2: Interviews and psychological tests at age 6. Natl Swed Environ Prot Bd, Rpt 3642 (Solna, Sweden). Kuntz, WD; Pitkin, RM; Bostrom, A; et al. (1982) Maternal and cord-blood background mercury levels: a longitudinal surveillance . Am J Obstet Gynecol 143:440-443. Kuhnert, PM; Kuhnert, BR; Erhard , P (1981) Comparison of mercury levels in maternal-blood, fetal cord-blood, and plac ental tissues. Am J Obst et Gynecol. 139(2):209-213. Lauwerys, R; Buchet, JP; Roels, H; et al. (1978) Placental transfer of le ad, mercury, cadmium, and carbon monoxide in women. I. Comparison of the frequency distributi ons of the biological indices in maternal and umbilical co rd-blood. Environ Res 15(2):278-289. 

### http://www.epa.gov/iris/subst/0073.htmLee, JH; Han, DH. (1995). Maternal and fetal toxicity of methylmercuric chloride ad ministered to pregnant Fischer 344 rats. J Toxic ol Environ Health 45(4):415-425. Marsh, DO; Clarkson, TW; Cox, C; et al. (1987) Fetal methylmercury po isoning: relationship between concentration in single strands of maternal-hair and chil d effects. Arch Neurol 44:1017- 1022. Miettinen, JK; Rahola, T; Hattula, T; et al. (1971). Eliminatio n of 203-Hg methylmercury in man. Ann Clin Res 3:116-122. Mitsumori, K; Hiarano, M; Ueda, H; et al. (1990) Chronic toxicity an d carcinogenicity of methylmercury chloride in B6C3F1 mi ce. Fundam Appl Toxicol 14:179-190. Myers, GJ; Marsh, DO; Cox, C; et al. (1995a) A pilot neurodevelopmental study of Seychellois children following in utero exposure to methylmercury from a maternal fish diet. Neurotoxicology 16(4):629-638. Myers, GJ; Marsh, DO; Davidson, PW. (1995b) Ma in neurodevelopmental study of Seychellois children following in utero exposure to methylmercury from a maternal fi sh diet: outcome at six months. Neurotoxicology 16(4):653-664. Myers, GJ; Davidson, PW; Cox, C; et al. (1995c ) Neurodevelopmetnal ou tcomes of Seychellois children sixty-six months after in utero exposure to methyl mercury from a maternal fish diet: pilot study. Neurotoxicology 16(4):639-652. Myers, GJ; Davidson, PW; Shamlaye, CF; et al . (1997) Effects of prenatal methylmercury exposure from a high fi sh diet on developmental milestones in the Seychelles Child Development Study. Neurotoxicology 18(3):819-830.

National Center for Health Statistics (NCHS). (1995) [Sec tion 4.2.3, body weight]. Newland, CM; Rasmussen, EB. ( 2000) Aging unmasks adverse effect s of gestational exposure to methylmercury in rats. Ne urotoxicol Teratol 22. Nishima, T; Ikeda, S; Tada, T; et al. (1977) Me rcury content levels in mother and newborn and their interrelation. Ann Rep To kyo Metro Res Lab PH 28:215-220.

National Research Counci l (NRC). (2000) Toxicolo gical effects of methyl mercury. Committee on the Toxicological Effects of Me thylmercury, Board on Environmental Studies and Toxicology, Commission on Life Sciences, National Research Council. Washington, DC: National Academy Press. Ong, CN; Chia, SE; Foo, SC; et al. (1993) Conc entrations of heavy metals in maternal and umbilical cord-blood. Biometals 6:61-66. Pitkin, RM; Bahns, JA; Filer, LJ , Jr; et al. (1976) Mercury in human maternal and cord-blood, placenta, and milk. Proc So c Exp Biol Me d 151(3):565-567. Ramirez, GB; Cruz, MCV; Pagulaya n, O; et al. (2000) The Tagum St udy: I. Analysis and clinical correlates of mercury in matern al and cord-blood, breast milk , meconium, and infants' hair. Pediatrics 106:774-781. 

### http://www.epa.gov/iris/subst/0073.htmRetzlaff, JA; Tauxe, WN; Khely, JM; et al. (1969) Erythrocyte vo lume, plasma volume, and lean body mass in adult men and women. Blood 33:649-664. Rice, DC. (1989) Delayed neurotox icity in monkeys exposed develo pmentally to me thylmercury. Neurotox 10:645-650. Rice, DC. (1996) Sensory and cogn itive effects of de velopmental methylmercury exposure in monkeys, and a comparison to effects in rodents. Neurot oxicology 17:139-154. Rice, DC. (1998) Age-related increase in auditoryimpairment in monkeys exposed in utero plus postnatally to methylmercury . Toxicol Sci 44(2):191-196. Rice, DC; Gilbert, SG. (1982) Early chronic low-level meth ylmercury poisoning in monkeys impairs spatial vision. Science 216:759-761. Rice, DC; Gilbert, SG. ( 1990) Effects of developmental exposureto methylmercury on spatial and temporal visual function in monkeys. Toxicol Appl Pharmacol 102:151-163. Rice, DC; Gilbert, SG. ( 1992) Exposure to methylmercury from birth to adulthood impairs highfrequency hearing in monkeys. To xicol Appl Pharmacol 102:151-163. Rice, DC; Gilbert, SG. ( 1995) Effects of developmental methylmercury exposure or lifetime lead exposure on vibration sensitiv ity function in monkeys. Toxic ol Appl Pharmacol 134(1):161-169. Rice, DC; Hayward, S. (1999) Comp arison of visual function at adulthood and during aging in monkeys exposed to lead or methyl mercury. Neuroto xicology 20:767-784. Salonen, JT; Seppanen, K; Nyyssonen, K; et al. (1995) Intake of me rcury from fish, lipid peroxidation, and the riskof myocardial infarction and corona ry, cardiovascular, and any death in Eastern Finnish men. Ci rculation 91(3):645-655. Sherlock, JC; Lindsay, DG; Hislop , J; et al. (1982) Duplication di et study on mercury intake by fish consumers in the United Kingdom. Arch Environ Health 37(5):271-278. Sherlock, J; Hislop, J; Newton, D; et al. (1984) Elevation of mercury in human blood from controlled chronic ingest ion of methylmercury in fish. Hum Toxicol 3:117-131. Sikorski, R; Paszkowski, T; Slaw inski, P; (1989) The intrapartum content of toxic metals in maternal-blood and umbilical cord -blood. Ginekol Pol 60(3):151-155. Smith, JC; Allen, PV; Turner, MD; et al. (1994) The kinetics of intravenously administered methylmercury in man. Toxico l Appl Pharmacol 128:251-256. Soong, Y-K; Tseng, R; Liu, C; et al. (1991) Lead, cadmiu m, arsenic and mercury levels in maternal and fetal cord-blood. J Formosan Med Assoc 90:59-65. Soria, ML; Sanz, P; Martinez, D; et al. (1992) Total mercury and methylmercury in hair, maternal and umbilical blood, and placenta from women in the Seville area. Bull Environ Contam Toxicol 48:494-501. Sørensen, N; Murata, K; Budtz-Jø rgensen, E; et al. (1999) Prenat al methylmercury exposure as a cardiovascular risk factor at seven years of age. Epidemiology 10:370-375. 

### http://www.epa.gov/iris/subst/0073.htmSpyker, JM. (1975) Assessing the im pact of low level chemicals on development: behavioral and latent effects. Fe d Proc 34(9):1835-1844. Stern, AH. (1997) Estimation of the interi ndividual variability in the one-compartment pharmacokinetic model for methylmercury: implicat ions for the derivation of a reference dose. Regul Toxicol Pharmacol 25:277-288. Steurwald, U; Weibe, P; Jorgen sen, K; (2000) Maternal seafoo d diet, methylmercury exposure, and neonatal neurologic func tion. J Pediatr 136(5):599-605. Suter, KE. (1975) Studies on the dominant lethal and fertility effects of the heavy metal compounds methyl mercuric hydroxide, mercuricchloride, and cadmium chloride in male and female mice. Mutat Res 30:365-374. Swartout, J; Rice, G. (2000) Uncert ainty analysis of the estimated ingestion rates used to derive the methylmercury refere nce dose. Drug Clin Toxicol 23(1):293-306. Truska, P; Rosival, I; Balazova, G; et al. (1989 ) Placental concentrations of cadmium, lead, and mercury in mothers and their newborns. J Hy g Epidemiol Microbiol Immunol 33(2):141-147. Tsuchiya, H; Mitani, K; Kodama, T; et al. (1984) Placental transfer of he avy metals in normal pregnant Japanese women. Arch Environ Health 39(1):11-17. U.S. EPA. (1980) Ambient Water Qua lity Criteria Document for Mercury. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Water Regulation and St andards, Washington, DC . EPA/440/5-80/058. NTIS PB 81-117699. U.S. EPA. (1984) Mercury Heal th Effects Update: Health I ssue Assessment. Final Report. Prepared by the Office of Health and Environ mental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Air Quality Pl anning and Standa rds, Research Triangle Park, NC. EPA/600/ 8-84/019F. NTIS PB81-85-123925. U.S. EPA. (1987) Peer ReviewWorkshop on Mercury Issues . Environmental Criteria and Assessment Office, Cincinnati, OH . Summary report. October 26-27. U.S. EPA. (1988) Drinking Water Criteria Document for Inorganic Mercury. Prepared by the Office of Health and Environmental Assessment, En vironmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington , DC. EPA/600/X-84/178. NTIS PB89- 192207. U.S. EPA. (1995) Mercury Study Report to Cong ress. Office of Research and Development, Washington, DC. External Revi ew Draft. EPA/600/P-94/002Ab. U.S. EPA. (1997) Mercury Study Report to Cong ress. Office of Research and Development, Washington, DC. December, 1997. U.S. EPA. (2001) Water Quality Criterion for th e Protection of Human Health: Methylmercury Chapter 4: Risk Assessment for Methylmercury. Office of Scie nce and Technology, Office of Water. 

### http://www.epa.gov/iris/subst/0073.htmVahter, M; Akesson, A; Lind, B; et al. (2000) Longitudinal stud y of methylmercury and inorganic mercury in blood and urine of pregnant and lactating women, as well as in umbilical cord-blood. Environ Res 84:186-194. WHO (World Health Organization). (1990) Enviro nmental Health Criteria 101: Methylmercury. Geneva. Yang, J; Jiang, Z; Wan, Y; et al. (1997) Mate rnal-fetal transfer of metallic mercury via the placenta and milk. Ann Clin Lab Sci 27(2):135-141.

_VI.B. Inhalation RfC References

None

_VI.C. CarcinogenicityAssessment References Betti, C., T. Davini an d R. Barale. 1992. Genoto xic activity of methyl mercury chloride and dimethyl mercury in huma n lymphocytes. Mutat. Res. 281(4): 255 260. Blakley, B.R. 1984. Enha ncement of urethane-induced adenom a formation in Swiss mice exposed to methylmercury. Can. J. Comp. Med. 48: 299 302. Charbonneau, S.M., I.C. Munro, E.A. Nera et al . 1976. Chronic toxicity of methylmercury in the adult cat. Toxicology. 5: 337-349. Costa, M., N.T. Christie, O. Cantoni, J.T. Zelikoff, X.W. Wang and T.G. Rossman. 1991. DNA damage by mercury compounds: An overview. In: Advances in Mercury Toxicity, T. Suzuki, N. Imura and T.W. Clarkson, Ed. Plenum Press, New York, NY. p. 255-273. Eriksson, M., L. Hardell, N.O. Berg, T. Moller and O. Axelson. 1981. Soft- tissue sarcomas and exposure to chemical substa nces: A case-referent study. Br. J. Ind. Med. 38: 27 33. Eriksson, M., L. Hardell and H.-O. Adami. 1990. Exposure to dioxins asa risk factor for soft-tissue sarcoma: A population -based case-control study. J. Natl. Cancer Inst. 82(6): 486 490. Fiskesjo, G. 1979. Two organic mercury compounds tested for mutagenicityin mammalian cells by use of the cell line V 79-4. Hereditas. 90: 103-109. Hardell, L. and M. Eriksson. 1988. The association between soft-tis sue sarcomas and exposure to phenoxyacetic acids. A new case-referent study. Cancer. 62: 652 656. Hardell, L., M. Eriksson, P. Lenner and E. Lundgren. 1981. Ma lignant lymphoma and exposure to chemicals, especially organic so lvents, chlorophenols and phenoxy acids: A case-control study. Br. J. Cancer. 43: 169 176. Heddle, J.R. and W.R. Bruce. 1977. Comparis on of the micronucleusand sperm assay for mutagenicity with the carcinogenic activities of 61 different agents. In: Origins of Human Cancer, H.H. Hiatt, J.D. Watson, J.A. Winsten, Ed. Vol. 4. Cold Spring Harbor Conferences. 

### http://www.epa.gov/iris/subst/0073.htmHirano, M., K. Mitsumori, K. Maita and Y. Sh irasu. 1986. Further carc inogenicity study on methylmercury chloride in ICR mice. Jpn. J. Vet. Sc i. 48(1): 127 135. Janicki, K., J. Dobrowolski and K. Krasnicki. 1987. Correlation between contam ination of the rural environment with me rcury and occurrence of leukemia in men and cattle. Ch emosphere. 16: 253 257. Jenssen, D. and C. Ramel. 1980. The micronucleus te st as part of a short- term mutagenicity test program for the prediction of carcinogenicity evaluated by 143 agents tested. Mutat. Res. 75: 191 202. Kanematsu, N., M. Hara and T. Kada. 1980. Rec assay and mutagenicity studies on metal compounds. Mutat. Res. 77: 109-116. Mailhes, J.B. 1983. Methylmercury effects on Syrian ha mster metaphase II oocyte chromosomes. Environ. Mutage n. 5: 679-686. Matsumoto, N. and A. Spindle. 1982. Sensitivity of earl y mouse embryos to methylmercury toxicity. Toxicol. Appl. Pharmacol. 64: 108-117. Miller, C.T., Z. Zawidska, E. Nagy and S.M. Char bonneau. 1979. Indicators of genetic toxicity in leukocytes and granulocytic precursors after chronic methylmercury in gestion by cats. Bull. Environ. Contam. To xicol. 21: 296-303. Mitsumori, K., K. Maita, T. Saito, S. Tsuda and Y. Shirasu. 1981. Carcinogenicity of methylmercury chloride in ICR mi ce: Preliminary note on renal ca rcinogenesis. Cancer Lett. 12: 305 310. Mitsumori, K., K. Takahashi, O. Matano, S. Goto and Y. Shirasu. 1983. Chronic toxicity of methylmercury chloride in rats: Clinical study an d chemical analysis. Jpn. J. Vet. Sci. 45(6): 747- 757. Mitsumori, K., K. Maita and Y. Sh irasu. 1984. Chronic toxicity of methylmercury chlo ride in rats: Pathological study. Jpn. J. Vet. Sci. 46(4): 549-557. Mitsumori, K., M. Hirano, H. Ueda, K. Maita and Y. Shiras u. 1990. Chronic toxicity and carcinogenicity of methylmercury chloride in B6C3F1 mice. Fund. Appl. Toxicol. 14: 179 190. Morimoto, K., S. Iijima and A. Ko izumi. 1982. Selenite pr events the induction of sister-chromatid exchanges by methyl mercury and mercuric chlori de in human whole-blood cultures. Mutat. Res. 102: 183-192. Munro, I., E. Nera, S. Charbo nneau, B. Junkins an d Z. Zawidzka. 1980. Chronic toxicity of methylmercury in the rat. J. Envi ron. Pathol. Toxicol. 3: 437-447. Nakai, S. and I. Machida. 1973. Genetic effect of organic mercury on yeast. Mutat. Res. 21(6): 348. Nakazawa, N., F. Makino and S. Okada. 1975. Acut e effects of mercuric compounds on cultured mammalian cells. Biochem. Pharmacol. 24: 489-493. 

### http://www.epa.gov/iris/subst/0073.htmNewberne, P.M., O. Glaser and L. Friedman. 1972. Chronic exposure of rats to methyl mercury in fish protein. Na ture. 237: 40-41. Ramel, C. 1972. Gene tic effects. In : Mercury in the Environment - An Epidemiological and Toxicological Appraisal, L. Friberg and J. Vostal, Ed. CRC Pre ss, Cleveland, OH. p. 169-181. (Cited in U.S. EPA, 1985). Schroeder, H. and M. Mitchener. 1975. Life-time effects of mercury, methyl mercury, and nine other trace metals in mi ce. J. Nutr. 105: 452 458. Skerfving, S., K. Hansson and J. Lindsten. 1970. Chromosome breakage in humans exposed to methyl mercury through fish consumption. Arch. Environ. Health. 21: 133-139. Skerfving, S., K. Hansson, C. Mangs, J. Lindsten and N. Ry man. 1974. Methyl mercury-induced chromosome damage in man. Environ. Res. 7: 83-98. Suter, K.E. 1975. Studies on the dominant-lethal and fertility effects of the heavy metal compounds methylmercuric hydro xide, mercuric chloride, and cadmium chloride in male and female mice. Mutat. Res. 30: 365-374. Tamashiro, H., M. Arakaki, H. Akagi, M. Futa tsuka and L.H. Roht. 1984. Causes of death in Minamata disease: Analysis of de ath certificates. Int. Arch. Occu p. Environ. Health. 54: 135-146. Tamashiro H., Arakaki M., Futa tsuka M. and E.S. Lee. 1986. Methylmercury exposure and mortality in southern Japan: A close look at ca uses of death. J. Epidemiol. Comm. Health. 40: 181-185. U.S. EPA. 1980. Ambient Water Quality Criteria Docu ment for Mercury. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Water Regulation and St andards, Washington, DC . EPA/440/5-80/058. NTIS PB81- 117699. U.S. EPA. 1984a. Mercury Health Effects Upda te: Health Issue Assessment. Final Report. Prepared by the Office of Health and Environ mental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Air Quality Pl anning and Standa rds, Research Triangle Park, NC. EPA/600/8- 84/019F. NTIS PB81-85-123925.

U.S. EPA. 1984b. Health Effects Assessment for Mercury. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Emergency and Remedial Response , Washington, DC. EPA/ 540/1086/042. NTIS PB86- 134533/AS. U.S. EPA. 1988. Drinking Water Cr iteria Document for Inorganic Me rcury. Prepared by the Office of Health and Environmental Assessment, En vironmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington , DC. EPA/600/X-84/178. NTIS PB89- 192207. U.S. EPA. 1993. Summary Review of Health Effects Associated wi th Mercuric Chloride: Health Issue Assessment (Draft). Prepared by the Offi ce of Health and Environmental Assessment, Environmental Criteria and Assessmen t Office, Cincinnati, OH for the Office of Air Quality Planning and Standards, Research Tria ngle Park, NC. EPA/600/R-92/199. 

### http://www.epa.gov/iris/subst/0073.htmDate Section Description U.S. EPA. 1995. Mercury Study Re port to Congress. Office of Research and Development, Washington, DC. External Revi ew Draft. EPA/600/P-94/002Ab. Verschuuren, H.G., R. Kroes, E.M. Den Tonkelaar et al. 1976. Toxicity of methylmercury chloride in rats. III. Long-term toxicity study. Toxicology. 6: 107 123. WHO (World Health Organization). 1990. Methyl mercury. Vol. 10 1. Geneva, Switzerland: World Health Organization, Distribution and Sales Se rvice, International Programme on Chemical Safety. Wulf, H.C., N. Kromann, N. Kousgaard, J.C. Ha nsen, E. Niebuhr and K. Alboge. 1986. Sister chromatid exchange (SCE) in Greenlandic eskimo s: Dose-response relationship between SCE and seal diet, smo king, and blood cadmium and mercury conc entrations. Sci. Total Environ. 48: 81- 94.



### _VII. Revision History Substance Name — Methylmercury (MeHg) CASRN — 22967-92-6

12/01/1988 I.A. Principal study citations added 02/01/1989 I.A. Oral RfD summa ry is being reevaluated 08/01/1991 VI. Bibliography on-line 01/01/1992 I.A.7. Secondary contact changed 01/01/1992 IV. Regulatory Action section on-line 03/01/1994 I.A.6. Work group review date added 04/01/1994 II. Carcinogenicity assessment now under review 09/01/1994 I.A.6. Work group review date added 10/01/1994 I.A.6. Work grou p review dates added 11/01/1994 I.A.6. Work group review date added 12/01/1994 I.A.6. Work grou p review date added 05/01/1995 I.A. Oral RfD summary replaced; new RfD 05/01/1995 VI.A. Oral RfD references replaced 05/01/1995 II. Carcinogenic ity assessment on-line 05/01/1995 VI.C. Carcinogenicity assessment references on-line 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. 07/27/2001 I.A., VI.A. Oral RfD Summary and references replaced

07/31/2001 VI.A. references corrected 

### http://www.epa.gov/iris/subst/0073.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 Chronic Inhalation

Exposure (RfC) • Inhalation RfC Summary • Principal and Supporting Studies • Uncertainty and Modifying Factors • Additional Studies/Comments 12/03/2002 I.A.6., II.D.2. Screening-Level Literature Review Findings message has been added.

04/05/2011 I.A.2. Edits made to dose conversion equations.



### _VIII. Synonyms Substance Name — Methylmercury (MeHg) CASRN — 22967-92-6 Last Revised — 07/27/2001

• 22967-92-6 • MeHg • Methylmercury • Methylmercury II • Mercury(1+), methyl- • Mercury (1+), Methyl-, Ion • Methyl Mercury • Methylmercury (II) Cation • Methylmercury Ion 

### http://www.epa.gov/iris/subst/0073.htm• 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, Review and, Contacts Bibliography Revision History Synonyms 

### http://www.epa.gov/iris/subst/0073.htm