#ll.	United States
Environmental Protection
^^LbI M % Agency
EPA/690/R-04/005F
Final
12-01-2004
Provisional Peer Reviewed Toxicity Values for
Dimethylmercury
(CASRN 593-74-8)
Derivation of Subchronic and Chronic Oral RfDs
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

-------
Acronyms and Abbreviations
bw	body weight
cc	cubic centimeters
CD	Caesarean Delivered
CERCLA	Comprehensive Environmental Response, Compensation and Liability Act
of 1980
CNS	central nervous system
cu.m	cubic meter
DWEL	Drinking Water Equivalent Level
FEL	frank-effect level
FIFRA	Federal Insecticide, Fungicide, and Rodenticide Act
g	grams
GI	gastrointestinal
HEC	human equivalent concentration
Hgb	hemoglobin
i.m.	intramuscular
i.p.	intraperitoneal
i.v.	intravenous
IRIS	Integrated Risk Information System
IUR	inhalation unit risk
kg	kilogram
L	liter
LEL	lowest-effect level
LOAEL	lowest-observed-adverse-effect level
LOAEL(ADJ)	LOAEL adjusted to continuous exposure duration
LOAEL(HEC)	LOAEL adjusted for dosimetric differences across species to a human
m	meter
MCL	maximum contaminant level
MCLG	maximum contaminant level goal
MF	modifying factor
mg	milligram
mg/kg	milligrams per kilogram
mg/L	milligrams per liter
MRL	minimal risk level
1

-------
MTD
maximum tolerated dose
MTL
median threshold limit
NAAQS
National Ambient Air Quality Standards
NOAEL
no-observed-adverse-effect level
NOAEL(ADJ)
NOAEL adjusted to continuous exposure duration
NOAEL(HEC)
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-observed-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
p-RfD
provisional oral reference dose
PBPK
physiologically based pharmacokinetic
PPb
parts per billion
ppm
parts per million
PPRTV
Provisional Peer Reviewed Toxicity Value
RBC
red blood cell(s)
RCRA
Resource Conservation and Recovery Act
RDDR
Regional deposited dose ratio (for the indicated lung region)
REL
relative exposure level
RfC
inhalation reference concentration
RfD
oral reference dose
RGDR
Regional gas dose ratio (for the indicated lung region)
s.c.
subcutaneous
SCE
sister chromatid exchange
SDWA
Safe Drinking Water Act
sq.cm.
square centimeters
TSCA
Toxic Substances Control Act
UF
uncertainty factor
Hg
microgram
|j,mol
micromoles
voc
volatile organic compound
11

-------
12-1-04
PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
DIMETHYLMERCURY (CASRN 593-74-8)
Derivation of Subchronic and Chronic Oral RfDs
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1.	EPA's Integrated Risk Information System (IRIS).
2.	Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund
Program.
3.	Other (peer-reviewed) toxicity values, including:
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are
developed according to a Standard Operating Procedure (SOP) and are derived after a review of
the relevant scientific literature using the same methods, sources of data, and Agency guidance
for value derivation generally used by the EPA IRIS Program. All provisional toxicity values
receive internal review by two EPA scientists and external peer review by three independently
selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multi-program consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all EPA programs, while PPRTVs are developed specifically for
the Superfund Program.
Because science and available information evolve, PPRTVs are initially derived with a
three-year life-cycle. However, EPA Regions (or the EPA HQ Superfund Program) sometimes
request that a frequently used PPRTV be reassessed. Once an IRIS value for a specific chemical
becomes available for Agency review, the analogous PPRTV for that same chemical is retired. It
should also be noted that some PPRTV manuscripts conclude that a PPRTV cannot be derived
based on inadequate data.
1

-------
12-1-04
Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and RCRA program offices are advised to carefully review the information provided
in this document to ensure that the PPRTVs used are appropriate for the types of exposures and
circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically
updated; therefore, users should ensure that the values contained in the PPRTV are current at the
time of use.
It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
A subchronic or chronic RfD for dimethylmercury is not available on IRIS (U.S. EPA,
2003), the HEAST (U.S. EPA, 1997a), or the Drinking Water Standards and Health Advisories
list (U.S. EPA, 2002). No relevant documents for dimethylmercury were located in the CARA
lists (U.S. EPA, 1991, 1994); however, several documents regarding mercury were listed,
including a Health Issue Assessment (U.S. EPA, 1984a), Health Effects Assessment (U.S. EPA,
1984b), Drinking Water Criteria Document (U.S. EPA, 1988), and Ambient Water Quality
Criteria Document (U.S. EPA, 1989). None of these documents derived an RfD for
dimethylmercury. The Mercury Study Report to Congress (U.S. EPA, 1997b) was also
consulted. ATSDR prepared a Toxicological Profile on Mercury (ATSDR, 1999) but did not
derive acute, intermediate, or chronic oral MRL values for dimethylmercury. IARC (1993)
produced a document for Mercury and Mercury Compounds where the Working Group
2

-------
12-1-04
considered methylmercury compounds including dimethylmercurypossibly carcinogenic to
humans (Group 2B), based on evidence that all methylmercury compounds are similar with
regard to absorption, distribution, metabolism, excretion, genotoxicity, and other forms of
toxicity. Neither NTP (2003) nor WHO (2003) have produced documents specific to
dimethylmercury. Literature searches of the following databases were conducted in 1993 for
dimethylmercury: TOXLIT (1985-1993), TOXLINE (1985-1993), HSDB, RTECS, TSCATS,
and CHEMID. Update literature searches were conducted from 1993 through October 2004:
TOXLINE (supplemented with BIOSIS andNTIS updates), CANCERLIT, MEDLINE, CCRIS,
GENETOX, HSDB, DART/ETICBACK, EMIC/EMICBACK, RTECS and TSCATS.
Alkylmercury compounds, such as dimethylmercury, are especially hazardous because of
their volatility, ability to penetrate epithelial and blood brain barriers, and their persistence in
vivo (Gosselin et al., 1984). Dimethylmercury is an extremely volatile liquid (boiling point = 96
C) (Budavari, 2001) that forms a toxic vapor. The vapor pressure of dimethylmercury at 23.7
C is 58.8 mm; a cubic meter of saturated air could hold more than 600 g of mercury (Toribara et
al., 1997). Oral toxicity assessments have been developed for a number of mercury compounds,
including, for example, mercuric chloride (CASRN 7487-94-7) (U.S. EPA, 2003) and
methylmercury (CASRN 22967-92-6) (U.S. EPA, 2003; ATSDR 1999).
REVIEW OF PERTINENT DATA
Human Studies
No data regarding the toxicity of dimethylmercury to humans following oral exposure
were located. However, several lethal accidental poisonings in humans exposed to
dimethylmercury by inhalation and/or dermal contact have been reported.
Dimethylmercury is highly lipophilic and rapidly absorbed through skin and semi-
permeable barriers, such as latex gloves (Blayney et al., 1997). Dimethylmercury is lethal at
doses of approximately 400 mg of Hg (equivalent to a few drops) or 5 mg/kg body weight
(Gosselin et al.,1984; Nierenberg et al., 1998).
Five fatalities involving 2 scientists and 3 technicians exposed to dimethylmercury have
occurred in chemical research laboratories. Subjects were exposed to dimethylmercury
transdermally while "handling" the mercuric compound or via inhaling the highly volatile vapors.
Although these accidental poisonings represent acute exposures, the delayed onset of
neurological symptoms post exposure and rapid demise thereafter, highlights the highly toxic
nature of this substance.
3

-------
12-1-04
A fatal accidental poisoning occurred when a 48 year-old research chemist spilled several
drops of liquid dimethylmercury onto the dorsum of her gloved hand while working under a
ventilated fume hood in the laboratory (Nierenberg et al., 1998; Siegler et al., 1999). Five
months later, and five days prior to hospital admission, the patient developed deterioration in
balance, gait, and speech. In the preceding two months, she had lost 6.8 kg (15 lb) and
experienced brief episodes of nausea, diarrhea, and abdominal discomfort. Initial medical
evaluation showed moderate upper-extremity dysmetria, dystaxic handwriting, dysarthria, and a
broad-based gait. Routine laboratory tests were normal and analyses of cerebrospinal fluid
reported clear fluid, protein concentration of 42 mg/dl, and no cells. Computed tomography (CT)
and magnetic resonance imaging (MRI) of the head were normal except for the incidental finding
of a probable menigioma, 1 cm in diameter. A preliminary whole blood mercury level was 4,000
jj,/L (normal range 1 to 10 jj,/L) collected 162 days after dimethylmercury exposure. The original
body burden was estimated to be 1,344 mg of mercury. Her condition worsened in subsequent
days; she described tingling in her fingers, brief flashes of light in her eyes, and soft background
noise in her ears that progressed to marked constriction of visual fields and deafness. The patient
lapsed into a coma 22 days from presentation of symptoms and died 4 months later, 298 days
after dimethylmercury exposure. The investigators attributed this accidental exposure to both
transdermal absorption of liquid dimethylmercury (given the lack of protection provided by the
disposable latex gloves) and inhalation of vapors (even though the work was conducted under a
fume hood). Upon gross examination, the areas of the brain most profoundly affected by
dimethylmercury poisoning were the cerebellum and visual cortex (Nierenberg et al., 1998).
Microscopic evaluation showed extensive neuronal loss and gliosis bilaterally within the primary
visual and auditory cortices, with milder loss of neurons and gliosis in the motor and sensory
cortices. There was widespread loss of cerebellar granular-cell neurons, Purkinje cells, and
basket-cell neurons, with evidence of loss of parallel fibers in the molecular layer. Bergmann
gliosis was well-developed and widespread.
The only previous report of neuropathology of dimethylmercury poisoning was by
Pezderova et al. (1974, as cited in Siegler et al., 1999), who reported the autopsy findings of a
28-year old chemist who had prepared 6000 grams of dimethylmercury over a 3 month period.
Additional exposure information was not provided. Neuropathologic damage included massive
Purkinje cell loss, temporal lobe damage, and slight degenerative changes of the granular layer,
but no changes in the cerebellar white matter.
Edwards (1865, 1866, as cited in Hunter et al., 1940) reported the poisoning of 3
laboratory technicians exposed to dimethylmercury while engaged in research. The route of
exposure was not provided, but is assumed to be primarily via inhalation with some dermal
exposure indicated for the second fatality. Two of the three technicians died. The first case, a
30-year old male, had been exposed to dimethylmercury for 3 months, when he began to
complain of numbness of the hands, deafness, poor vision, and sore gums. Symptoms exhibited
were described as "slow and dull in manner, unsteady in gait, and inability to stand without
4

-------
12-1-04
support." His condition deteriorated rapidly, including restlessness, unresponsiveness to
questions, urinary incontinence, and coma. The first technician died 2 weeks after reported onset
of symptoms. The second technician, a 23-year old male, had worked in the laboratory for 12
months and had reportedly "handled" dimethylmercury 3 months previous for a 2 week period.
One month after this exposure, he began complaining of sore gums, salivation, numbness of the
feet, hands and tongue, and dimness of vision. The second technician experienced similar
symptoms as the first in that he answered questions "only very slowly and with indistinct
speech," and was ataxic. After 3 weeks, the man had difficulty in swallowing, was incontinent,
unable to speak, and often restless and violent. He remained "in a confused state" until his death
due to pneumonia 12 months later. The third technician was described as having similar, less
severe symptoms, with eventual recovery.
Animal Studies
No data regarding the toxicity of dimethylmercury to animals following oral exposure
were located.
Two abstracts were located regarding a study or studies of the toxicity of
dimethylmercury following intramuscular administration to rats (Koya and Kudo, 1986; Koya et
al., 1986). Both abstracts were presented at the same scientific meeting in Tokyo, Japan, and
were very poorly translated; full reports of the studies do not appear to have been published. The
first abstract reported that 7 male Wistar rats were treated with 16 daily doses (route of treatment
not reported, but specified as intramuscular in the following abstract) of 1 mg Hg/rat/day as
dimethylmercury (Koya and Kudo, 1986). Following treatment, the rats were observed for 2 to
13 months. Neurological symptoms included ataxic gait, tremor, hypermetria, and loss of
equilibrium. Other effects included crossing of the hind limbs induced by holding the rat upside
down, twisting of the body, stretched knee and ankle junction, and raised and stiff tail. Muscle
atrophy and increased length of the hind limb claws were also reported. Examination of the brain
after sacrifice revealed a lesion described as focal calcification in the rostral vermis of the
cerebellum in the middle to basal part of the granular layer. The authors attributed the ataxia in
the rats to dimethylmercury-induced damage in this area of the brain. The second abstract by the
same authors describes a study essentially identical in protocol, and specifies the route of
administration as intramuscular injection (Koya et al., 1986). This abstract mentions an ataxic
gait, but focuses on histopathological findings. The brain lesions were as reported by Koya and
Kudo (1986): focal calcification in the rostral vermis of the cerebellum in the middle to basal part
of the granular layer. However, additional details were reported regarding the exact location of
the damage and the size of the calcified deposits. In addition, degeneration of the spino-
cerebellar and sensory tracts, and peripheral nerves was reported, with this damage possibly
occurring before that observed in the brain (Koya et al., 1986).
5

-------
12-1-04
In a more recent study from the same laboratory, Mori et al. (2000) administered 5 mg/kg
of dimethylmercury daily via intramuscular injection for 12 consecutive days to 20 adult female
Wistar rats, of which two were selected for sacrifice on each of days 1, 4, 7, 10, 12, 24, 32, 49,
100 and 140 post treatment. Of the total three control rats treated with sesame oil, one was
sacrificed on each of days 7, 24, and 100. On day 4, pyknotic neurons were found in the dorsal
root ganglia, cerebellar cortex, cerebral cortex and thalamus of treated rats. On day 10, necrotic
neurons were also found in the dorsal caudate nucleus, putamen and anterior horn of the spinal
cord. Neurohistological examination identified widespread calcium deposition in the nervous
system of treated rats as early as 4 days post-treatment. Behavioral observations in treated rats
were hind limbs that showed flexion and/or crossing on day 4, and from day 14, ataxic gait that
worsened over time.
No information or toxicological studies regarding the reproductive or developmental
effects of dimethylmercury were located.
Other Studies
Oyama et al. (1998) compared the reactivity of methylmercury, methylmercury
conjugated to L-cysteine, and dimethylmercury in vitro via flow cytometry methods. Reactivity
was measured by changes in intracellular calcium concentrations indicative of cell viability in rat
cerebellar neurons dissected from 10 to 14 day old Wistar rats treated with respective mercurial
compounds. Intracellular calcium was released from treated cerebellar neurons by
methylmercury and to a lesser extent by methylmercury-cysteine conjugate, but not by
dimethylmercury, including that it does not decrease viability in this assay.
Aggregating cell cultures of fetal rat telencephalon treated continuously with
dimethylmercury preferentially affected the mature cells compared to immature cells by
measurement of enzymatic activities and change in total protein content (Monnet-Tschudi et al.,
1993), although the toxicological significance of this finding in vivo is not known.
Dimethylmercury (10 "6 M) preferentially affected the differentiated cells from the aggregating
cell cultures during the range of culture days 24 to 34 (period of advanced development),
producing a 30% reduction in 2' 3' -cyclic nucleotide 3'-phosphohyrolase (CNP) activity. In the
immature cultures, days 5 to 14 (period of cell proliferation and early differentiation),
dimethylmercury treatment (10 "7 to 10"8) resulted in an approximate 60% increase in CNP
activity. Selective changes in the mature (fetal rat) cultures suggests dimethylmercury interferes
with neurological development at more advanced stages.
Ostland (1969; cited in Nierenberg et al., 1998) reported on the metabolism of
methylmercury and dimethylmercury in mice. Results indicated that dimethylmercury does not
enter the brain until metabolized over a period of days to monomethylmercury, which is capable
of binding to cellular proteins.
6

-------
12-1-04
FEASIBILITY OF DERIVING PROVISIONAL SUBCHRONIC AND CHRONIC
RfDs FOR DIMETHYLMERCURY
The database for dimethylmercury is inadequate for derivation of a p-RfD. No data on
the effects of oral exposure to dimethylmercury in animals or humans were located.
Derivation of a p-RfD for dimethylmercury by analogy to methylmercury was considered.
Limited data suggest that dimethylmercury does not enter the brain until metabolized to
monomethylmercury, which may produce toxicity by binding to cellular proteins (Ostland, 1969).
Support for methylmercury as the proximal toxicant in dimethylmercury poisoning comes from
Oyama et al. (1998), who found that methylmercury, but not dimethylmercury, was toxic to
cerebellar neurons in vitro. However, the human data suggest that dimethylmercury is more
acutely toxic than methylmercury. Methylmercury poisonings generally show gliosis of both the
cerebral and cerebellar cortices and damage consistent with granule and Golgi cell loss in the
cerebellum (Verity, 1997), but they do not show the massive Purkinje cell loss and temporal lobe
damage observed in the victims of dimethylmercury poisoning. The difference in
neuropathology may reflect differences in route and duration of exposure (the methylmercury
poisonings resulted from repeated consumption of contaminated food, in contrast to the
dimethylmercury poisonings, which resulted from single or short-term dermal/inhalation
exposure), or differences in toxicity between methyl and dimethylmercury. Additional data on
toxicity, toxicokinetics, and mode of action for both methyl and dimethylmercury would be
needed to support use of methylmercury as a surrogate for derivation of an p-RfD for
dimethylmercury.
REFERENCES
ATSDR (Agency for Toxic Substances and Disease Registry). 1999. Toxicological Profile on
Mercury. U.S. Department of Health and Human Services, Public Health Service. Atlanta, GA.
PB/99/142416). Online, http://www.atsdr.cdc.gov/toxprofiles/tp46.html
Blayney, M.B., J.S. Winn, and D.W. Nierenberg. 1997. Chemical Safety: handling
dimethylmercury. Chem. Eng. News. May 12; 75:7
Budavari, S. 2001. The Merck Index. Thirteenth edition. Merck & Co. Inc., Whitehouse
Station, NJ. p. 1091.
Edwards, G.N. 1865. St. Barth. Hosp. Rep. i. 141. (Cited in Hunter et al., 1940)
Edwards, G.N. 1866. St. Barth. Hosp. Rep. ii. 211. (Cited in Hunter et al., 1940)
7

-------
12-1-04
Gosselin, R.E., R.P. Smith and H.C. Hodge. 1984. Mercury. In: Clinical Toxicology of
Commercial Products. Fifth edition. Williams and Wilkins, Baltimore, p. 262 -275.
Hunter, D., R.R. Bomford and D.S. Russell. 1940. Poisoning by methylmercury compounds.
Quart. J. Med. 9: 193-213.
Koya, G. and M. Kudo. 1986. The correlation of characteristic cerebellar signs with the
localized lesion of the survived rats with dimethylmercury induced aftertrouble (sic). Fourth
International Congress of Toxicology, Tokyo, Japan. Toxicol. Lett. (Amst.). 31 (Suppl.): 144.
Koya, G., M. Kudo and M. Yoshimoto. 1986. Neural pathway from origin of lesion induced by
dimethylmercury to calcified rostral cerebellar vermal cortex. Fourth International Congress of
Toxicology, Tokyo, Japan. Toxicol. Lett. (Amst.). 31 (Suppl.): 145.
I ARC (International Agency for Research on Cancer). 1993. IARC Agents and Summary
Evaluations Mercury and Mercury Compounds. Online, http://www-cie.iarc.fr/
Monnet-Tschudi, F., M.-G. Zurich and P. Honegger. 1993. Evaluation of the toxicity of
different metal compounds in the developing brain using aggregating cell cultures as a model.
Tox. Vitro. 7(4): 335-339.
Mori, F., K. Tanji and K. Wakabayashi. 2000. Widespread calcium deposits, as detected using
the alizarin red S technique, in the nervous system of rats treated with dimethylmercury.
Neuropathology. 20: 210-215.
Nierenberg, D.W., R.E. Nordgren, M.B. Chang et al. 1998. Delayed cerebellar disease and
death after accidental exposure to dimethylmercury. N. Engl. J. Med. 338: 1672-1676.
NTP (National Toxicology Program). 2003. Management Status Report. Online.
http://ntp-server.niehs.nih.gov/
Ostland, K. 1969. Studies on the metabolism of methylmercury and dimethylmercury in mice.
Acta. Pharmacol. Toxicol. 27: Supp 11. (Cited in Nierenberg et al., 1998)
Oyama, Y., M. Nakata, M Sakamoto et al. 1998. Methylmercury toxicity in dissociated rat brain
neurons: modification by L-cysteine and trimethylbenzylmercaptan and comparison with
dimethylmercury and N-ethylmalemide. Environ. Toxicol. Pharmacol. 6: 221-227.
Pezderova, J., A. Jirasek, M. Mraz and J. Pechan. 1974. Post-mortem findings and clinical signs
of dimethylmercury poisoning in man. Int. Arch. Arbeitsmed. 33:323-328. (Cited in
Nierenberg et al., 1998; Siegler et al., 1999)
8

-------
12-1-04
Siegler, R.W., D.W. Nierenberg, and W.F. Hickey. 1999. Fatal poisoning from liquid
dimethylmercury: a neuropathologic study. Human Pathology. 30(6): 720-723.
Toribara, T.Y., T.W. Clarkson and D.W. Nierenberg. 1997. Chemical Safety: more on working
with dimethylmercury. Chem. Eng. News. June 16; 75:6.
U.S. EPA. 1984a. Mercury Health Effects Update: Health Issue Assessment. Office of Health
and Environmental Assessment, Environmental Criteria and Assessment Office, Office of
Research and Development, Research Triangle Park, NC. EPA-600/8-84/019F. Final Report.
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 Solid Waste and Emergency Response, Washington, DC. NTIS PB 86-
134533/AS.
U.S. EPA. 1988. Drinking Water Criteria Document for Mercury. Prepared by the Office of
Health and Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Drinking Water, Washington, DC.
U.S. EPA. 1989. Ambient Water Quality 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 Regulations and Standards, Washington, DC.
U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. April.
U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. December.
U.S. EPA. 1997a. Health Effects Assessment Summary Tables. FY-1997 Update. Prepared by
the Office of Research and Development, National Center for Environmental Assessment,
Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC. July.
EPA/540/R-97/036. NTIS PB97-921199.
U.S. EPA. 1997b. Mercury Study Report to Congress. Volume V: Health Effects of Mercury
and Mercury Compounds. Office of Research and Development, Washington, DC. December.
EPA-452/R-97-007.
U.S. EPA. 2002. 2002 Edition of the Drinking Water Standards and Health Advisories. Office
of Water, Washington, DC. EPA 822-R-02-038. Online.
http://www.epa.gov/waterscience/drinking/standards/dwstandards.pdf
9

-------
12-1-04
U.S. EPA. 2003. Integrated Risk Information System (IRIS). Office of Research and
Development, National Center for Environmental Assessment, Washington, DC. Online.
http ://www. epa. gov/ iris/
Verity, M.A. 1997. Toxic disorders. In: Greenfield's Neuropathology. Sixth edition. London,
Arnold, p. 756-811. (Cited in Siegler et al., 1999)
WHO (World Health Organization). 2003. Online Catalogs for the Environmental Criteria
Series. Online, http://www.who.int/pcs/pubs/pub ehc alph.htm
10

-------
12-1-04
Provisional Peer Reviewed Toxicity Values for
Dimethylmercury
(CASRN 593-74-8)
Derivation of Subchronic and Chronic Inhalation RfCs
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

-------
Acronyms and Abbreviations
bw	body weight
cc	cubic centimeters
CD	Caesarean Delivered
CERCLA	Comprehensive Environmental Response, Compensation and Liability Act
of 1980
CNS	central nervous system
cu.m	cubic meter
DWEL	Drinking Water Equivalent Level
FEL	frank-effect level
FIFRA	Federal Insecticide, Fungicide, and Rodenticide Act
g	grams
GI	gastrointestinal
HEC	human equivalent concentration
Hgb	hemoglobin
i.m.	intramuscular
i.p.	intraperitoneal
i.v.	intravenous
IRIS	Integrated Risk Information System
IUR	inhalation unit risk
kg	kilogram
L	liter
LEL	lowest-effect level
LOAEL	lowest-observed-adverse-effect level
LOAEL(ADJ)	LOAEL adjusted to continuous exposure duration
LOAEL(HEC)	LOAEL adjusted for dosimetric differences across species to a human
m	meter
MCL	maximum contaminant level
MCLG	maximum contaminant level goal
MF	modifying factor
mg	milligram
mg/kg	milligrams per kilogram
mg/L	milligrams per liter
MRL	minimal risk level
1

-------
MTD
maximum tolerated dose
MTL
median threshold limit
NAAQS
National Ambient Air Quality Standards
NOAEL
no-observed-adverse-effect level
NOAEL(ADJ)
NOAEL adjusted to continuous exposure duration
NOAEL(HEC)
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-observed-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
p-RfD
provisional oral reference dose
PBPK
physiologically based pharmacokinetic
PPb
parts per billion
ppm
parts per million
PPRTV
Provisional Peer Reviewed Toxicity Value
RBC
red blood cell(s)
RCRA
Resource Conservation and Recovery Act
RDDR
Regional deposited dose ratio (for the indicated lung region)
REL
relative exposure level
RfC
inhalation reference concentration
RfD
oral reference dose
RGDR
Regional gas dose ratio (for the indicated lung region)
s.c.
subcutaneous
SCE
sister chromatid exchange
SDWA
Safe Drinking Water Act
sq.cm.
square centimeters
TSCA
Toxic Substances Control Act
UF
uncertainty factor
Hg
microgram
|j,mol
micromoles
voc
volatile organic compound
11

-------
12-1-04
PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
DIMETHYLMERCURY (CASRN 593-74-8)
Derivation of Subchronic and Chronic Inhalation RfCs
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1.	EPA's Integrated Risk Information System (IRIS).
2.	Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund
Program.
3.	Other (peer-reviewed) toxicity values, including:
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are
developed according to a Standard Operating Procedure (SOP) and are derived after a review of
the relevant scientific literature using the same methods, sources of data, and Agency guidance
for value derivation generally used by the EPA IRIS Program. All provisional toxicity values
receive internal review by two EPA scientists and external peer review by three independently
selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multi-program consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all EPA programs, while PPRTVs are developed specifically for
the Superfund Program.
Because science and available information evolve, PPRTVs are initially derived with a
three-year life-cycle. However, EPA Regions (or the EPA HQ Superfund Program) sometimes
request that a frequently used PPRTV be reassessed. Once an IRIS value for a specific chemical
becomes available for Agency review, the analogous PPRTV for that same chemical is retired. It
should also be noted that some PPRTV manuscripts conclude that a PPRTV cannot be derived
based on inadequate data.
1

-------
12-1-04
Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and RCRA program offices are advised to carefully review the information provided
in this document to ensure that the PPRTVs used are appropriate for the types of exposures and
circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically
updated; therefore, users should ensure that the values contained in the PPRTV are current at the
time of use.
It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
A subchronic or chronic RfC for dimethylmercury is not available on IRIS (U.S. EPA,
2003) or in the HEAST (U.S. EPA, 1997a). No relevant documents for dimethylmercury were
located in the CARA lists (U.S. EPA, 1991, 1994); however, several documents regarding
mercury were listed, including a Health Issue Assessment (U.S. EPA, 1984a), Health Effects
Assessment (U.S. EPA, 1984b), Drinking Water Criteria Document (U.S. EPA, 1988), and
Ambient Water Quality Criteria Document (U.S. EPA, 1989). None of these documents derived
an RfC for dimethylmercury. The Mercury Study Report to Congress (U.S. EPA, 1997b) was
also consulted. ATSDR prepared a Toxicological Profile on Mercury (ATSDR, 1999) but did
not derive acute, intermediate, or chronic inhalation MRL values for dimethylmercury. IARC
(1993) produced a document for Mercury and Mercury Compounds where the Working Group
considered methylmercury compounds including dimethylmercury possibly carcinogenic to
2

-------
12-1-04
humans (Group 2B), based on evidence that all methylmercury compounds are similar with
regard to absorption, distribution, metabolism, excretion, genotoxicity, and other forms of
toxicity. Dimethylmercury is included in the group of the organo (alkyl) mercury compounds for
which OSHA (2003) set a TWA-PEL of 0.01 mg/m3 and ACGIH (2003) adopted a TWA-TLV of
0.01 mg/m3 as Hg and a STEL of 0.03 mg/m3 as Hg. NIOSH (2002) has not recommended an
exposure limit for this compound. The California Office of Environmental Health and Hazard
Assessment (OEHHA, 2002) and the Air Resources Board (ARB) support a chronic inhalation
REL of 1.0 |J.g/m3 for "methylmercury [CASRN 593-74-8]" based on potential adverse effects to
the nervous system. Neither NTP (2003) nor WHO (2003) have produced documents specific to
dimethylmercury. Literature searches of the following databases were conducted in 1993 for
dimethylmercury: TOXLU (1985-1993), TOXLINE (1985-1993), HSDB, RTECS, TSCATS,
and CHEMID. Update literature searches were conducted from 1993 through October 2004:
TOXLINE (supplemented with BIOSIS and NTIS updates), CANCERLIT, MEDLINE, CCRIS,
GENETOX, HSDB, DART/ETICBACK, EMIC/EMICBACK, RTECS and TSCATS.
The alkyl mercury compounds, such as dimethylmercury, are especially hazardous
because of their volatility, ability to penetrate epithelial and blood brain barriers, and their
persistence in vivo (Gosselin et al.,1984). Dimethylmercury is an extremely volatile liquid
(boiling point = 96 C) (Budavari, 2001) that forms a toxic vapor upon contact with air. The
vapor pressure of dimethylmercury at 23.7 C is 58.8 mm; a cubic meter of saturated air could
hold more than 600 g of mercury (Toribara et al., 1997). Dimethylmercury is highly lipophilic
and rapidly absorbed through skin and semi-permeable barriers, such as latex gloves (Blayney et
al, 1997). Dimethylmercury is lethal at doses of approximately 400 mg of Hg (equivalent to a
few drops) or 5 mg/kg body weight (Gosselin et al.,1984; Nierenberg et al., 1998).
REVIEW OF THE PERTINENT DATA
Human Studies
No data regarding the toxicity of dimethylmercury to humans following chronic or
subchronic inhalation exposures were located. However, several accidental poisonings in
humans by dimethylmercury have been reported.
Five fatalities involving 2 scientists and 3 technicians exposed to dimethylmercury have
occurred in chemical research laboratories. Subjects were exposed to dimethylmercury
transdermally while "handling" the mercuric compound or via inhaling the highly volatile vapors.
Although these accidental poisonings represent acute exposures, the delayed onset of
neurological symptoms post exposure and rapid demise thereafter, provides information to the
highly toxic nature of this substance.
3

-------
12-1-04
A fatal accidental poisoning occurred when a 48 year-old research chemist spilled several
drops of liquid dimethylmercury onto the dorsum of her gloved hand while working under a
ventilated fume hood in the laboratory (Nierenberg et al., 1998; Siegler et al., 1999). Five
months later, and five days prior to hospital admission, the patient developed deterioration in
balance, gait, and speech. In the preceding two months, she had lost 6.8 kg (15 lb) and
experienced brief episodes of nausea, diarrhea, and abdominal discomfort. Initial medical
evaluation showed moderate upper-extremity dysmetria, dystaxic handwriting, dysarthria, and a
broad-based gait. Routine laboratory tests were normal and analyses of cerebrospinal fluid
reported clear fluid, protein concentration of 42 mg/dl, and no cells. Computed tomography (CT)
and magnetic resonance imaging (MRI) of the head were normal except for the incidental finding
of a probable menigioma, 1 cm in diameter. A preliminary whole blood mercury level was 4,000
jj,/L (normal range 1 to 10 jj,/L) collected 162 days after dimethylmercury exposure. The original
body burden was estimated to be 1,344 mg of mercury. Her condition worsened in subsequent
days; she described tingling in her fingers, brief flashes of light in her eyes, and soft background
noise in her ears that progressed to marked constriction of visual fields and deafness. The patient
lapsed into a coma 22 days from presentation of symptoms and died 4 months later, 298 days
after dimethylmercury exposure. The investigators attributed this accidental exposure to both
transdermal absorption of liquid dimethylmercury (given the lack of protection provided by the
disposable latex gloves) and inhalation of vapors (even though the work was conducted under a
fume hood).
Upon gross examination, the areas of the brain most profoundly affected by
dimethylmercury poisoning were the cerebellum and visual cortex (Nierenberg et al., 1998).
Microscopic evaluation showed extensive neuronal loss and gliosis bilaterally within the primary
visual and auditory cortices, with milder loss of neurons and gliosis in the motor and sensory
cortices. There was widespread loss of cerebellar granular-cell neurons, Purkinje cells, and
basket-cell neurons, with evidence of loss of parallel fibers in the molecular layer. Bergmann
gliosis was well-developed and widespread.
The only previous report of neuropathology of dimethylmercury poisoning was by
Pezderova et al. (1974, as cited in Siegler et al., 1999), who reported the autopsy findings of a
28-year old chemist who had prepared 6000 grams of dimethylmercury over a 3 month period.
Additional exposure information was not provided. Neuropathologic damage included massive
Purkinje cell loss, temporal lobe damage, and slight degenerative changes of the granular layer,
but no changes in the cerebellar white matter.
Edwards (1865, 1866, as cited in Hunter et al., 1940) reported the poisoning of 3
laboratory technicians exposed to dimethylmercury while engaged in research. The route of
exposure was not provided, but is assumed to be primarily via inhalation with some dermal
exposure indicated for the second fatality. Two of the three technicians died. The first case, a
30-year old male, had been exposed to dimethylmercury for 3 months, when he began to
4

-------
12-1-04
complain of numbness of the hands, deafness, poor vision, and sore gums. Symptoms exhibited
were described as "slow and dull in manner, unsteady in gait, and inability to stand without
support." His condition deteriorated rapidly, including restlessness, unresponsiveness to
questions, urinary incontinence, and coma. The first technician died 2 weeks after reported onset
of symptoms. The second technician, a 23-year old male, had worked in the laboratory for 12
months and had reportedly "handled" dimethylmercury 3 months previous for a 2 week period.
One month after this exposure, he began complaining of sore gums, salivation, numbness of the
feet, hands and tongue, and dimness of vision. The second technician experienced similar
symptoms as the first in that he answered questions "only very slowly and with indistinct
speech," and was ataxic. After 3 weeks, the man had difficulty in swallowing, was incontinent,
unable to speak, and often restless and violent. He remained "in a confused state" until his death
due to pneumonia 12 months later. The third technician was described as having similar, less
severe symptoms, with eventual recovery.
Animal Studies
No data regarding the toxicity of dimethylmercury to animals following inhalation
exposure were located.
Two abstracts were located regarding a study or studies of the toxicity of
dimethylmercury following intramuscular administration to rats (Koya and Kudo, 1986; Koya et
al., 1986). Both abstracts were presented at the same scientific meeting in Tokyo, Japan, and
were very poorly translated; full reports of the studies do not appear to have been published. The
first abstract reported that 7 male Wistar rats were treated with 16 daily doses (route of treatment
not reported, but specified as intramuscular in the following abstract) of 1 mg Hg/rat/day as
dimethylmercury (Koya and Kudo, 1986). Following treatment, the rats were observed for 2 to
13 months. Neurological symptoms included ataxic gait, tremor, hypermetria, and loss of
equilibrium. Other effects included crossing of the hind limbs induced by holding the rat upside
down, twisting of the body, stretched knee and ankle junction, and raised and stiff tail. Muscle
atrophy and increased length of the hind limb claws were also reported. Examination of the brain
after sacrifice revealed a lesion described as focal calcification in the rostral vermis of the
cerebellum in the middle to basal part of the granular layer. The authors attributed the ataxia in
the rats to dimethylmercury-induced damage in this area of the brain. The second abstract by the
same authors describes a study essentially identical in protocol, and specifies the route of
administration as intramuscular injection (Koya et al., 1986). This abstract mentions an ataxic
gait, but focuses on histopathological findings. The brain lesions were as reported by Koya and
Kudo (1986): focal calcification in the rostral vermis of the cerebellum in the middle to basal part
of the granular layer. However, additional details were reported regarding the exact location of
the damage and the size of the calcified deposits. In addition, degeneration of the spino-
cerebellar and sensory tracts, and peripheral nerves was reported, with this damage possibly
occurring before that observed in the brain (Koya et al., 1986).
5

-------
12-1-04
In a more recent study from the same laboratory, Mori et al. (2000) administered 5 mg/kg
of dimethylmercury daily via intramuscular injection for 12 consecutive days to 20 adult female
Wistar rats, of which two were selected for sacrifice on each of days 1, 4, 7, 10, 12, 24, 32, 49,
100 and 140 post treatment. Of the total three control rats treated with sesame oil, one was
sacrificed on each of days 7, 24, and 100. On day 4, pyknotic neurons were found in the dorsal
root ganglia, cerebellar cortex, cerebral cortex and thalamus of treated rats. On day 10, necrotic
neurons were also found in the dorsal caudate nucleus, putamen and anterior horn of the spinal
cord. Neurohistological examination identified widespread calcium deposition in the nervous
system of treated rats as early as 4 days post-treatment. Behavioral observations in treated rats
were hind limbs that showed flexion and/or crossing on day 4, and from day 14, ataxic gait that
worsened over time.
No information or toxicological studies regarding the reproductive or developmental
effects of dimethylmercury were located.
Other Studies
Oyama et al. (1998) compared the reactivity of methylmercury, methylmercury
conjugated to L-cysteine, and dimethylmercury in vitro via flow cytometry methods. Reactivity
was measured by changes in intracellular calcium concentrations indicative of cell viability in rat
cerebellar neurons dissected from 10 to 14 day old Wistar rats treated with respective mercurial
compounds. Intracellular calcium was released from treated cerebellar neurons by
methylmercury and to a lesser extent by methylmercury-cysteine conjugate, but not by
dimethylmercury.
Aggregating cell cultures of fetal rat telencephalon treated continuously with
dimethylmercury preferentially affected the mature cells compared to immature cells by
measurement of enzymatic activities and change in total protein content (Monnet-Tschudi et al.,
1993). Dimethylmercury (10 "6 M) preferentially affected the differentiated cells from the
aggregating cell cultures during the range of culture days 24 to 34 (period of advanced
development), producing a 30% reduction in 2' 3' -cyclic nucleotide 3'-phosphohyrolase (CNP)
activity. In the immature cultures, days 5 to 14 (period of cell proliferation and early
differentiation), dimethylmercury treatment (10 "7 to 10"8) resulted in an approximate 60%
increase in CNP activity. Selective changes in the mature (fetal rat) cultures suggests
dimethylmercury interferes with neurological development at more advanced stages.
Ostland (1969; cited in Nierenberg et al., 1998) reported on the metabolism of
methylmercury and dimethylmercury in mice. Results indicated that dimethylmercury does not
enter the brain until metabolized over a period of days to monomethylmercury, which is capable
of binding to cellular proteins.
6

-------
12-1-04
FEASIBILITY OF DERIVING PROVISIONAL SUBCHRONIC AND CHRONIC
RfCs FOR DIMETHYLMERCURY
The inhalation data base for dimethylmercury is inadequate for p-RfC derivation. No
subchronic or chronic data examining effects of inhalation exposure to dimethylmercury in
animals or humans were located.
Derivation of a p-RfC for dimethylmercury by analogy to methylmercury was considered,
but no RfC for methylmercury is available on IRIS (U.S. EPA, 2003).
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 2003. 2003 Threshold
Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices.
Cincinnati, OH.
ATSDR (Agency for Toxic Substances and Disease Registry). 1999. Toxicological Profile on
Mercury. U.S. Department of Health and Human Services, Public Health Service. Atlanta, GA.
PB/99/142416). Online, http://www.atsdr.cdc.gov/toxprofiles/tp46.html
Blayney, M.B., J.S. Winn and D.W. Nierenberg. 1997. Chemical Safety: handling
dimethylmercury. Chem. Eng. News. May 12; 75:7
Budavari, S. 2001. The Merck Index. Thirteenth edition. Merck & Co. Inc., Whitehouse
Station, NJ. p. 1091.
Edwards, G.N. 1865. St. Barth. Hosp. Rep. i. 141. (Cited in Hunter et al., 1940)
Edwards, G.N. 1866. St. Barth. Hosp. Rep. ii. 211. (Cited in Hunter et al., 1940)
Gosselin, R.E., R.P. Smith and H.C. Hodge. 1984. Mercury. In: Clinical Toxicology of
Commercial Products. Fifth edition. Williams and Wilkins, Baltimore, p. 262 -275.
Hunter, D., R.R. Bomford and D.S. Russell. 1940. Poisoning by methylmercury compounds.
Quart. J. Med. 9: 193-213.
Koya, G. and M. Kudo. 1986. The correlation of characteristic cerebellar signs with the
localized lesion of the survived rats with dimethylmercury induced aftertrouble (sic). Fourth
International Congress of Toxicology, Tokyo, Japan. Toxicol. Lett. (Amst.). 31 (Suppl.): 144.
7

-------
12-1-04
Koya, G., M. Kudo and M. Yoshimoto. 1986. Neural pathway from origin of lesion induced by
dimethylmercury to calcified rostral cerebellar vermal cortex. Fourth International Congress of
Toxicology, Tokyo, Japan. Toxicol. Lett. (Amst.). 31 (Suppl.): 145.
I ARC (International Agency for Research on Cancer). 1993. IARC Agents and Summary
Evaluations Mercury and Mercury Compounds. Online, http://www-cie.iarc.fr/
Monnet-Tschudi, F., M.-G. Zurich, and P. Honegger. 1993. Evaluation of the toxicity of
different metal compounds in the developing brain using aggregating cell cultures as a model.
Tox. Vitro. 7(4): 335-339.
Mori, F., K. Tanji and K. Wakabayashi. 2000. Widespread calcium deposits, as detected using
the alizarin red S technique, in the nervous system of rats treated with dimethylmercury.
Neuropathology. 20: 210-215.
Nierenberg, D.W., R.E. Nordgren, M.B. Chang et al. 1998. Delayed cerebellar disease and
death after accidental exposure to dimethylmercury. N. Engl. J. Med. 338: 1672-1676.
NIOSH (National Institute for Occupational Safety and Health). 2002. NIOSH Pocket Guide to
Chemical Hazards. Online. http://www.cdc.gOv/niosh/npg/npgd0000.html#F
NTP (National Toxicology Program). 2003. Management Status Report. Online.
http://ntp-server.niehs.nih.gov/
Office of Environmental Health and Hazard Assessment (OEHHA). 2002. OEHHA Approved
Chronic Reference Exposure Levels and Target Organs. State of California. Online.
http://www.arb. ca. gov/toxics/healthval/chronic.pdf
OSHA (Occupational Safety and Health Administration). 2003. OSHA Standard 1910.1000
TableZ-1. Part Z, Toxic and Hazardous Substances. Online.
http://www.osha-slc.gov/OshStd data/1910 1000 TABLE Z-l.html
Ostland, K. 1969. Studies on the metabolism of methylmercury and dimethylmercury in mice.
Acta. Pharmacol. Toxicol. 27: Supp 11. (Cited in Nierenberg et al., 1998)
Oyama, Y., M. Nakata, M Sakamoto et al. 1998. Methylmercury toxicity in dissociated rat brain
neurons: modification by L-cysteine and trimethylbenzylmercaptan and comparison with
dimethylmercury and N-ethylmalemide. Environ. Toxicol. Pharmacol. 6: 221-227.
Pezderova, J., A. Jirasek, M. Mraz, and J. Pechan. 1974. Post-mortem findings and clinical
signs of dimethylmercury poisoning in man. Int. Arch. Arbeitsmed. 33:323-328. (Cited in
Nierenberg et al., 1998; Siegler et al., 1999)
8

-------
12-1-04
Siegler, R.W., D.W. Nierenberg and W.F. Hickey. 1999. Fatal poisoning from liquid
dimethylmercury: a neuropathologic study. Human Pathology. 30(6): 720-723.
Toribara, T.Y., T.W. Clarkson and D.W. Nierenberg. 1997. Chemical Safety: more on working
with dimethylmercury. Chem. Eng. News. June 16; 75:6.
U.S. EPA. 1984a. Mercury Health Effects Update: Health Issue Assessment. Office of Health
and Environmental Assessment, Environmental Criteria and Assessment Office, Office of
Research and Development, Research Triangle Park, NC. EPA-600/8-84/019F. Final Report.
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 Solid Waste and Emergency Response, Washington, DC. NTIS PB 86-
134533/AS.
U.S. EPA. 1988. Drinking Water Criteria Document for Mercury. Prepared by the Office of
Health and Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Drinking Water, Washington, DC.
U.S. EPA. 1989. Ambient Water Quality 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 Regulations and Standards, Washington, DC.
U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. April.
U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. December.
U.S. EPA. 1997a. Health Effects Assessment Summary Tables. FY-1997 Update. Prepared by
the Office of Research and Development, National Center for Environmental Assessment,
Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC. July.
EPA/540/R-97/036. NTIS PB97-921199.
U.S. EPA. 1997b. Mercury Study Report to Congress. Volume V: Health Effects of Mercury
and Mercury Compounds. Office of Research and Development, Washington, DC. December.
EPA-452/R-97-007.
U.S. EPA. 2003. Integrated Risk Information System (IRIS). Office of Research and
Development, National Center for Environmental Assessment, Washington, DC. Online.
http://www.epa.gov/iris/
9

-------
12-1-04
WHO (World Health Organization). 2003. Online Catalogs for the Environmental Criteria
Series. Online, http://www.who.int/pcs/pubs/pub ehc alph.htm
10

-------
12-1-04
Provisional Peer Reviewed Toxicity Values for
Dimethylmercury
(CASRN 593-74-8)
Derivation of a Carcinogenicity Assessment
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

-------
Acronyms and Abbreviations
bw	body weight
cc	cubic centimeters
CD	Caesarean Delivered
CERCLA	Comprehensive Environmental Response, Compensation and Liability Act
of 1980
CNS	central nervous system
cu.m	cubic meter
DWEL	Drinking Water Equivalent Level
FEL	frank-effect level
FIFRA	Federal Insecticide, Fungicide, and Rodenticide Act
g	grams
GI	gastrointestinal
HEC	human equivalent concentration
Hgb	hemoglobin
i.m.	intramuscular
i.p.	intraperitoneal
i.v.	intravenous
IRIS	Integrated Risk Information System
IUR	inhalation unit risk
kg	kilogram
L	liter
LEL	lowest-effect level
LOAEL	lowest-observed-adverse-effect level
LOAEL(ADJ)	LOAEL adjusted to continuous exposure duration
LOAEL(HEC)	LOAEL adjusted for dosimetric differences across species to a human
m	meter
MCL	maximum contaminant level
MCLG	maximum contaminant level goal
MF	modifying factor
mg	milligram
mg/kg	milligrams per kilogram
mg/L	milligrams per liter
MRL	minimal risk level
1

-------
MTD
maximum tolerated dose
MTL
median threshold limit
NAAQS
National Ambient Air Quality Standards
NOAEL
no-observed-adverse-effect level
NOAEL(ADJ)
NOAEL adjusted to continuous exposure duration
NOAEL(HEC)
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-observed-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
p-RfD
provisional oral reference dose
PBPK
physiologically based pharmacokinetic
PPb
parts per billion
ppm
parts per million
PPRTV
Provisional Peer Reviewed Toxicity Value
RBC
red blood cell(s)
RCRA
Resource Conservation and Recovery Act
RDDR
Regional deposited dose ratio (for the indicated lung region)
REL
relative exposure level
RfC
inhalation reference concentration
RfD
oral reference dose
RGDR
Regional gas dose ratio (for the indicated lung region)
s.c.
subcutaneous
SCE
sister chromatid exchange
SDWA
Safe Drinking Water Act
sq.cm.
square centimeters
TSCA
Toxic Substances Control Act
UF
uncertainty factor
Hg
microgram
|j,mol
micromoles
voc
volatile organic compound
11

-------
12-1-04
PROVISIONAL PEER REVIEWED TOXICITY VALUE FOR
DIMETHYLMERCURY (CASRN 593-74-8)
Derivation of a Carcinogenicity Assessment
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1.	EPA's Integrated Risk Information System (IRIS).
2.	Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund
Program.
3.	Other (peer-reviewed) toxicity values, including:
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are
developed according to a Standard Operating Procedure (SOP) and are derived after a review of
the relevant scientific literature using the same methods, sources of data, and Agency guidance
for value derivation generally used by the EPA IRIS Program. All provisional toxicity values
receive internal review by two EPA scientists and external peer review by three independently
selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multi-program consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all EPA programs, while PPRTVs are developed specifically for
the Superfund Program.
Because science and available information evolve, PPRTVs are initially derived with a
three-year life-cycle. However, EPA Regions (or the EPA HQ Superfund Program) sometimes
request that a frequently used PPRTV be reassessed. Once an IRIS value for a specific chemical
becomes available for Agency review, the analogous PPRTV for that same chemical is retired. It
should also be noted that some PPRTV manuscripts conclude that a PPRTV cannot be derived
based on inadequate data.
1

-------
12-1-04
Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and RCRA program offices are advised to carefully review the information provided
in this document to ensure that the PPRTVs used are appropriate for the types of exposures and
circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically
updated; therefore, users should ensure that the values contained in the PPRTV are current at the
time of use.
It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
A carcinogenicity assessment for dimethylmercury is not available on IRIS (U.S. EPA,
2003), the HEAST (U.S. EPA, 1997a), or the Drinking Water Standards and Health Advisories
list (U.S. EPA, 2002). No relevant documents for dimethylmercury were located in the CARA
lists (U.S. EPA, 1991, 1994); however, several documents regarding mercury were listed,
including a Health Issue Assessment (U.S. EPA, 1984a), Health Effects Assessment (U.S. EPA,
1984b), Drinking Water Criteria Document (U.S. EPA, 1988), and Ambient Water Quality
Criteria Document (U.S. EPA, 1989). None of these documents provided an assessment of
carcinogenicity for dimethylmercury. The Mercury Study Report to Congress (U.S. EPA, 1997b)
and ATSDR (1999) Toxicological Profile for Mercury were also consulted. IARC (1993)
produced a document for Mercury and Mercury Compounds where the Working Group
considered methylmercury compounds including dimethylmercury possibly carcinogenic to
2

-------
12-1-04
humans (Group 2B), based on evidence that all methylmercury compounds are similar with
regard to absorption, distribution, metabolism, excretion, genotoxicity, and other forms of
toxicity. Neither NTP (2003) nor WHO (2003) have produced documents specific to
dimethylmercury. Literature searches of the following databases were conducted in 1993 for
dimethylmercury: TOXLIT (1985-1993), TOXLINE (1985-1993), HSDB, RTECS, TSCATS,
and CHEMID. Update literature searches were conducted from 1993 through October 2004:
TOXLINE (supplemented with BIOSIS and NTIS updates), CANCERLIT, MEDLINE, CCRIS,
GENETOX, HSDB, DART/ETICBACK, EMIC/EMICBACK, RTECS and TSCATS.
The alkylmercury compounds, such as dimethylmercury, are especially hazardous
because of their volatility, ability to penetrate epithelial and blood brain barriers, and their
persistence in vivo (Gosselin et al.,1984). Dimethylmercury is an extremely volatile liquid
(boiling point = 96 C) (Budavari, 2001) that forms a toxic vapor upon contact with air. The
vapor pressure of dimethylmercury at 23.7 C is 58.8 mm; a cubic meter of saturated air could
hold more than 600 g of mercury (Toribara et al., 1997). Dimethylmercury is highly lipophilic
and rapidly absorbed through skin and semi-permeable barriers, such as latex gloves (Blayney et
al, 1997).
REVIEW OF THE PERTINENT DATA
Human Studies
No data regarding the possible carcinogenicity of dimethylmercury in humans were
located.
Animal Studies
No reports of animal studies examining the carcinogenicity of dimethylmercury by any
route of exposure were located.
Other Studies
Dimethylmercury induced chromosomal aberrations and aneuploidy in cultured human
lymphocytes (Betti et al., 1992), and DNA damage (DNA fragmentation measured via single-cell
microgel electrophoresis) in human lymphocytes, rat lymphocytes, and rat gastric mucosa cells in
vitro (Betti et al., 1993). Dimethylmercury also induced chromosomal aberrations in cultured
CHO cells, but did not potentiate the clastogenic effects of mitomycin c, cisplatin, 4-
nitroquinoline 1-oxide, or methyl methanesulfonate in this test system (Yamada et al., 1993).
3

-------
12-1-04
In vivo and in vitro studies examining the effects of mercury on meiosis (Jagiello and Lin,
1973) were conducted in the ova removed from random bred Swiss/Webster female mice. Ova
were treated in vitro with 0, 2.5, 5, 10, or 25 )J.g/ml of dimethylmercury for 5 hours to obtain first
metaphase meiotic figures or 14 hours to obtain second metaphase with polar body. An
increased number of abnormal divisions occurred in the second metaphase in cultures containing
10 jag dimethylmercury; no cell division occurred in cultures with 25 jag. Treatment of 6 female
mice via intravenous administration of 1400 jag Hg/g body weight of dimethylmercury did not
result in an increased number of abnormalities in either stage of meiosis in the ova removed from
donor females, cultured, and examined for meiotic figures 24 hours post treatment. The U.S.
EPA's Gene-Tox Program (U.S. EPA, 1981) Work Group evaluated the findings of Jagiello and
Lin (1973) and concluded that they were qualitatively negative for clastogenic effects (Preston et
al 1981).
A dominant lethal assay was conducted in 20 random bred Swiss male mice injected
intraperitoneally with 50 mg dimethylmercury/kg;10 males were injected with the vehicle,
petroleum, and served as controls (Varma et al., 1974). An increased mutagenicity index (MI)
occurred in the post-meiotic stages of spermatogenesis, indicative of genetic damage to
spermatozoa and spermatids; this resulted in reduced fertility and decreased number of implants
per pregnancy. The Gene-Tox Work Group on the Dominant Lethal Assay (U.S. EPA, 1985)
evaluated the experimental protocol for in vivo mammalian genotoxicity studies based on
established criteria. The Work Group concluded the findings by Varma et al. (1974) indicate a
borderline response (considered positive in the estimation of correlation between mutagenicity
and carcinogenicity) (Green et al., 1985).
PROVISIONAL WEIGHT-OF-EVIDENCE CLASSIFICATION
No studies examining the carcinogenic potential of dimethylmercury in humans or
animals were located. Limited genotoxicity data indicate dimethylmercury can produce DNA
damage and chromosomal aberrations in vitro, but these effects have not been demonstrated in
vivo. As the available data are insufficient to assess carcinogenic potential in animals or humans,
they are consistent with the hazard descriptor, "inadequate information to assess carcinogenic
potential," as specified by the proposed U.S. EPA (1999) Guidelines for Carcinogen Risk
Assessment. It should be noted that methylmercury was determined to be a possible human
carcinogen in the Mercury Study Report to Congress (U.S. EPA, 1997b).
QUANTITATIVE ESTIMATES OF CARCINOGENIC RISK
Derivation of quantitative estimates of cancer risk for dimethylmercury is precluded by
the lack of data demonstrating carcinogenicity associated with dimethylmercury exposure.
4

-------
12-1-04
REFERENCES
ATSDR (Agency for Toxic Substances and Disease Registry). 1999. Toxicological Profile on
Mercury. U.S. Department of Health and Human Services, Public Health Service. Atlanta, GA.
PB/99/142416). Online, http://www.atsdr.cdc.gov/toxprofiles/tp46.html
Betti, C., T. Davini and R. Barale. 1992. Genotoxic activity of methylmercury chloride and
dimethylmercury in human lymphocytes. Mutat. Res. 281:255-260.
Betti, C., R. Barale and B.L. Pool-Zobel. 1993. Comparative studies on the cytotoxicity and
genotoxic effects of two organic mercury compounds in lymphocytes and gastric mucosa cells of
Sprague-Dawley rats. Environ. Mol. Mutagen. 22(3): 172-180.
Blayney, M.B., J.S. Winn and D.W. Nierenberg. 1997. Chemical Safety: handling
dimethylmercury. Chem. Eng. News. May 12; 75:7
Budavari, S. 2001. The Merck Index. Thirteenth edition. Merck & Co. Inc., Whitehouse
Station, NJ. p. 1091.
Gosselin, R.E., R.P. Smith and H.C. Hodge. 1984. Mercury. In: Clinical Toxicology of
Commercial Products. Fifth edition. Williams and Wilkins, Baltimore, p. 262 -275.
Green, S., A. Augletta, J. Fabricant et al. 1985. Current status of bioassays in genetic
toxicology-the dominant lethal assay. A report of the U.S. Environmental Protection Agency
Gene-Tox Program. Mutat. Res. 154:49-67.
I ARC (International Agency for Research on Cancer). 1993. IARC Agents and Summary
Evaluations Mercury and Mercury Compounds. Online, http://www-cie.iarc.fr/
Jagiello, G. and J.S. Lin. 1973. An assessment of the effects of mercury on the meiosis of
mouse ova. Mutat. Res. 17: 93-99.
NTP (National Toxicology Program). 2003. Management Status Report. Online.
http://ntp-server.niehs.nih.gov/
Preston, R.J., W. Au, M.A. Bender et al. 1981. Mammalian in vivo and in vitro cytogenetic
assays: A report of the U.S. EPA's gene-tox program. Mutat. Res. 87: 143-188.
Toribara, T.Y., T.W. Clarkson and D.W. Nierenberg. 1997. Chemical Safety: more on working
with dimethylmercury. Chem. Eng. News. June 16; 75:6.
5

-------
12-1-04
U.S. EPA. 1981. Mammalian in Vivo and in Vitro Cytogenetic Assays: a Report Prepared by
the Gene-Tox Work Group on Mammalian in Vivo and in Vitro Cytogenetics Assays for the
Gene-Tox Program, Office of Toxic Substances, Office of Pesticides and Toxic Substances. U.S.
EPA., Washington, DC.
U.S. EPA. 1984a. Mercury Health Effects Update: Health Issue Assessment. Office of Health
and Environmental Assessment, Environmental Criteria and Assessment Office, Office of
Research and Development, Research Triangle Park, NC. EPA-600/8-84/019F. Final Report.
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 Solid Waste and Emergency Response, Washington, DC. NTIS PB 86-
134533/AS.
U.S. EPA. 1985. Current Status of Bioassays in Genetic Toxicology- the Dominant Lethal
Assay. A Report Prepared by the Gene-Tox Work Group on the Dominant Lethal Assay for the
Gene-Tox Program, Office of Toxic Substances, Office of Pesticides and Toxic Substances. U.S.
EPA., Washington, DC.
U.S. EPA. 1988. Drinking Water Criteria Document for Mercury. Prepared by the Office of
Health and Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Drinking Water, Washington, DC.
U.S. EPA. 1989. Ambient Water Quality 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 Regulations and Standards, Washington, DC.
U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. April.
U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. December.
U.S. EPA. 1997a. Health Effects Assessment Summary Tables. FY-1997 Update. Prepared by
the Office of Research and Development, National Center for Environmental Assessment,
Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC. July.
EPA/540/R-97/036. NTIS PB97-921199.
U.S. EPA. 1997b. Mercury Study Report to Congress. Volume V: Health Effects of Mercury
and Mercury Compounds. Office of Research and Development, Washington, DC. December.
EPA-452/R-97-007.
6

-------
12-1-04
U.S. EPA. 1999. Proposed Guidelines for Cancer Risk Assessment. July 1999. Office of
Research and Development, National Center for Environmental Assessment, Washington, DC.
U.S. EPA. 2002. 2002 Edition of the Drinking Water Standards and Health Advisories. Office
of Water, Washington, DC. EPA 822-R-02-038. Online.
http://www.epa.gov/waterscience/drinking/standards/dwstandards.pdf
U.S. EPA. 2003. Integrated Risk Information System (IRIS). Office of Research and
Development, National Center for Environmental Assessment, Washington, DC. Online.
http://www.epa.gov/iris/
Varma, M.M., E.L. Sage, and S.R. Joshi. 1974. Mutagenicity following administration of
dimethylmercury in swiss male mice. J. Environ. Sys. 4(2): 135-142.
WHO (World Health Organization). 2003. Online Catalogs for the Environmental Criteria
Series. Online, http://www.who.int/pcs/pubs/pub ehc alph.htm
Yamada, H., T. Miyahara, H. Kozuka et al. 1993. Potentiating effects of organomercuries on
clastogen-induced chromosome aberrations in cultured Chinese hamster cells. Mutat. Res. 290:
281-291.
7

-------