revised final - Agency for Toxic Substances and Disease Registry ...

MERCURY 219
2. HEALTH EFFECTS
extracellular Ca ++ and the mobilization of Ca ++ from intracellular stores (perhaps the endoplasmic
reticulum and mitochondria), whereas HgCl 2 causes only an increased influx of extracellular Ca ++ .
2.4.3 Animal-to-Human Extrapolations
Mechanisms for the end toxic effects of inorganic and organic mercury are believed to be similar, and the
differences in parent compound toxicity result from difference in the kinetics and metabolism of the parent
compound. Animal models generally reflect the toxic events observed in humans (i.e., neurological for
methylmercury toxicity and the kidneys for inorganic mercury); however, there are species and strain
differences in response to mercury exposure. Prenatal exposures in animals result in neurological damage
to the more sensitive developing fetus as is the case in humans. The observed inter- and intraspecies
differences in the type and severity of the toxic response to mercury may result from differences in the
absorption, distribution, transformation, and end tissue concentration of the parent mercury compound.
For example, C57BL/6, B10.D2, B10.S inbred mice accumulated higher concentrations of mercury in the
spleen than A.SW, and DBA/2 strains, subjected to the same dosage regimen. The higher concentration of
splenic mercury in C57BL/6, B10.D2, B10.S correlated with the increased susceptibility of these strains to
a mercury chloride-induced systemic autoimmune syndrome. The lower splenic mercury in A.SW, and
DBA/2 strains resulted in more resistance to an autoimmune response (Griem et al. 1997).
A better understanding of certain physiological and biochemical processes affecting mercury kinetics may
help explain these species differences. Specific processes that appear likely determinants include
differences in demethylation rates affecting methylmercury fecal secretion, reabsorption, and membrane
transport (Farris et al. 1993); differences in tissue glutathione content and renal γ-glutamyltranspeptidase
activity (Tanaka et al. 1991, 1992), differences in antioxidative status (Miller and Woods 1993),
differences in plasma cysteine concentrations compared with other thiol-containing amino acids (Aschner
and Clarkson 1988; Clarkson 1995), and differences in factors that could affect gut lumenal uptake
(Foulkes and Bergman 1993; Urano et al. 1990). Better controls and reporting of dietary factors, volume
and timing of doses, and housing conditions would assist in the comparisons of effects among species and
strains.
Further development of PBPK/PBPD models will assist in addressing these differences and in
extrapolating animal data to support risk assessments for mercury exposure in humans.