Current EPA Guidelines Require Updated Uncertainty Factors

The guidelines on risk assessment of neurotoxic agents (EPA 1998) clearly indicate that an uncertainty factor of ten should be applied when attempting to extrapolate a lowest-observed adverse-effect-level (LOAEL) to establish an REL, as is the case for studies of mercury vaportoxicity – the threshold cannot be determined from available studies.

The guidelines on risk assessment of neurotoxic agents also clearly indicate that an uncertainty factor of ten should be applied to address inter-individual variability in susceptibility to the toxic effects of neurotoxinssuch as mercury vapor.

This would create a total uncertainty factor adjustment of 100.

The EPA RfC for mercury vapor, which predates EPA’s 1998 guidance on the risk assessment ofneurotoxins, only applied a total uncertainty adjustment of thirty, an adjustment now out of compliance with EPA policies.

Further modifying factors may also be considered by the EPA when they re-assessmercury vapor neurotoxicity, that modifying factor addressing other deficiencies and limitationsin the toxicological database on mercury vapor. Those deficiencies and limitations may include,but not be limited to, the following:

Gender Differences in Hg Pharmacokinetics

Recent evidence indicates clear gender differences in uptake, distribution, and excretionof Hg°. Studies indicate that males metabolize and eliminate Hg° more quickly than do femalesand that, after exposure, Hg° tends to be distributed differently in males and females, with agreater proportion of dose going to the brain and CNS of females. While Hg° appears to bedistributed more quickly to the kidney and urine in males, it appears to be retained for a longertime in females and thus be potentially more available to illicit toxic response in females.

Several authors have indicated that gender is an important factor in the metabolic andtoxicologic response to exposure to chemicals (Calabrese, 1986; Silvaggio and Mattison, 1994;Gochfeld, 1997; Iyaniwura, 2004). There is evidence that males and females respond differentlyto Hg° exposure, in terms of uptake, distribution, and toxicity. As discussed below, studiesexamining both genders have exhibited differing accumulation patterns in males and females, andfaster elimination rates in males. These differences may result in variable, gender-related toxicresponse to Hg° exposure. The available data, however, are limited and inadequate to reliablyquantify gender-related differences in toxicity.

It should be noted that both organic (methyl Hg) and inorganic forms of Hg wereconsidered in this review of gender-specific response because once across the blood-brain barrierthe ultimate biochemical fate of the ionic Hg moiety (Hg2+ from organic and inorganic Hg) isidentical (Lorscheider et al., 1995). FDA completely fails to account for this additional bodyburden when comparing exposure to the RfC and MRL.

Hongo et al. (1994) examined urinary Hg excretion by university staff and students whowere occasionally exposed to Hg° vapor over a period of six years. Regression analysis indicatedthat the Hg° vapor exposure level was the major variable predicting urinary Hg excretion, butgender (along with age and the presence of amalgam fillings) was also reported to be an importantfactor. They did not, however, specifically quantify the gender-related differences.

Jokstad (1990) surveyed the Norwegian Dental Association to assess the significance ofpotential sources of Hg exposure. Urinary Hg excretion values were correlated to answers onthe survey. In addition to correlations between environment and practice characteristics and Hgexcretion values, the data indicated that urinary Hg excretion might be gender-dependent, due tothe fact that the mean UHg levels of 849 participants were slightly lower in women compared tomen (40 nmol/L versus 44 nmol/L). When a group of female assistants with higher exposures wereexcluded from the analysis, the average UHg concentration for women dropped to 38 nmol/L.The authors reported, “[n]either the length of work experience, nor the years in the current officefacility correlate[d] with the urinary Hg levels.” While there was a correlation between UHgconcentrations and the number of hours spent per week in the clinic for the entire group and for the male participants, this correlation was not observed when female participants were evaluated alone. The mean Hg concentrations for females remained relatively constant and, for the most part, were lower than those measured in the male participants, especially at the higher exposure levels. The authors did not offer a definitive conclusion as to whether their results support gender dependency in absorption or excretion.

At an annual American Dental Association (ADA) meeting, Kaste, et al. (1992) presenteda study of dentists and dental assistants who had been evaluated for Hg exposure. Over 4000participants (7.6% women) answered questionnaires and provided urine samples. There was asmall difference in average UHg concentration (4.9 μg/L in women and 6.3 μg/L in men). Thisvariation might, however, be attributable to the number of years of exposure as Kaste, et al. (1992)reported an average of 8.2 years in practice for the female participants and an average of 19.2years in practice for the males.

Pamphlett, et al. (1997) compared the uptake of inorganic Hg by motor neurons inmale and female mice and measured Hg concentrations in their kidneys. Significantly moreneurons contained Hg granules in female mice than in male mice, and kidneys of male micehad significantly higher amounts of Hg when compared to the females. Pamphlett et al. (1997)concluded that the decreased deposition of Hg in the kidneys of the female mice resulted in anincrease in circulating Hg, which was available for neuron uptake.

Pamphlett & Coote (1998) were interested in identifying the lowest dose of Hg vapor thatresulted in Hg deposition in neurons, and in determining if female neurons were more susceptibleto Hg vapor toxicity than male neurons. After a 50 μg/m3 dose, Hg was observed in the spinalmotor neurons of female mice at half the exposure time (6 hours) necessary for it to be observedin the spinal motor neurons of male mice (12 hours).

Nielsen & Anderson (1990) investigated the effects of different dose levels and routesof administration on whole body retention and relative organ distribution of Hg chloride intwo strains of female mice. In addition, the authors investigated gender differences in thedistribution of Hg chloride by comparing their results to a previous study with male mice (Nielsen& Andersen, 1989). This comparison showed that similar fractions of Hg body burden weredistributed in the liver of males and females, while a significantly larger fraction of Hg bodyburden was deposited in the kidneys of the male mice than in female mice.

Thomas, et al. (1986) examined the integrated exposures of tissues of female and malerats to organic and inorganic Hg. While whole body comparisons indicated that integratedexposures of males and females to inorganic Hg were equal, this study demonstrated that theintegrated exposure of the brain of female rats to inorganic Hg was 2.19 times that of the males.This finding suggested that there was a gender-related difference in the accumulation and/orretention of inorganic Hg in the central nervous system.

Miettnen (1973 as cited in Thomas, et al. 1986) reported that, in humans, the wholebody half time for Hg elimination following ingestion of protein bound Hg chloride was faster infemales than in males.

Hirayama & Yasutake (1986) and Yasutake & Hirayama (1988) studied C57BL/6N andBALB/cA mice to evaluate the mechanisms for gender-related differences in the in vivo fate ofmethyl Hg. A single administration of methyl Hg chloride in mature mice resulted in higher levelsof Hg in urine of males than of females. Five minutes after exposure, Hg levels in male kidneyswere higher than in female kidneys and these higher male concentrations were still in evidenceafter 24 hours. Lower Hg values were reported in other tissues of males when compared withfemales. After 24 hours, the Hg levels in urine were 6.5 times higher in males than in females.The levels of Hg in kidneys for males were higher than in females whereas the females had higherHg levels in the brain, liver and plasma. Castrated males had Hg tissue levels similar to femalesexcept in the brain and castrated females exhibited decreased urinary excretion of Hg. The authorsconcluded, “tissue distribution and urinary excretion of the administered methyl Hg seem to besubject to sex hormone control. This study demonstrates that the metabolism and elimination ofmethyl Hg occur significantly faster in males and that the sequence of events leading to urinaryexcretion of methyl Hg may proceed under the control of sex hormones.”

Magos et al. (1981) compared the sensitivity of female and male rats to methyl Hg. “Afteridentical doses the brains of females always contained more Hg than those of males. Female ratsdeveloped more intensive co-ordination disorders and after five doses they had more extensivedamage in the granular layer of the cerebellum than males.” However, the regional distribution ofHg within the brain was the same in males and females. The elimination rate in male kidneys wasfound to be significantly faster (16 day half-life) than the elimination rate for female kidneys (37day half-life).

Nielsen and Andersen (1991) found the route of methyl Hg administration did not affectthe whole-body retention of Hg significantly but that female mice retained more Hg than did malemice. Kidney deposition in males was twice that in females, and the male mice excreted Hgsignificantly faster than did the females.

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