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TOXICOLOGICAL SCIENCES 59, 291–296 (2001)
Copyright 2001 by the Society of Toxicology
Mercury Vapor and Female Reproductive Toxicity B. J. Davis,*,1 H. C. Price,† R. W. O’Connor,† R. Fernando,‡ A. S. Rowland,* and D. L. Morgan* *National Institute of Environmental Sciences, MD A2-01, Research Triangle Park, North Carolina 27709; †ManTech Environmental Technology, Inc., Research Triangle Park, North Carolina 27709; and ‡Research Triangle Institute, Research Triangle Park, North Carolina 27709 Received June 22, 2000; accepted October 16, 2000 mercury switches in children’s shoes that light up, and in Epidemiological studies finding menstrual cycle abnormalities
dental amalgams (ATSDR, 1997). Elemental Hg° is poorly among women occupationally exposed to Hg° prompted us to
absorbed by the dermal and oral routes. However, because it is investigate the mechanisms of reproductive toxicity of Hg° in the
highly volatile, the primary route of human exposure is by female rat. Nose-only Hg° vapor inhalation exposures were con-
inhalation of Hg° vapors. Inhaled Hg° vapor easily crosses the ducted on regularly cycling rats 80 –90 days of age in dose-re-
sponse and acute time-course studies, which have previously
pulmonary capillary membranes and can accumulate in distal proven useful as a model to identify ovarian toxicants. Vaginal
smears were evaluated daily and serum hormone levels were
The tissue distribution of Hg is similar after inhalation of correlated with cycle and with ovarian morphology at necropsy.
Hg° vapors or after ingestion of inorganic mercuric salts Exposure concentration–related effects of Hg° were evaluated by
(Hayes and Rothstein, 1962; Rothstein and Hayes, 1960).
exposing rats to 0, 1, 2, or 4 mg/m3 Hg° vapor 2 h/day for 11
However, because Hg° more readily penetrates cellular mem- consecutive days. Tissue Hg levels correlated with exposure con-
branes than inorganic mercuric salts, inhalation of Hg° vapors centration and duration. Exposure of rats to 4 mg/m3 (but not 1 or
results in greater Hg accumulation in all tissues. Intracellular 2 mg/m3) Hg vapor for 11 days resulted in significant decreases in
Hg° is rapidly oxidized by cytosolic catalase to mercuric mer- body weights relative to controls. Estrous cycles were slightly
cury (Hg2ϩ), the reactive species for most Hg compounds.
prolonged in the 2 and 4 mg/m3 dose groups, and serum estradiol
and progesterone levels were significantly different in the 4 mg/m3
Hg2ϩ can be formed by oxidation of Hg°, reduction of mercuric group compared to controls. The alterations in cycle and hor-
salts, or demethylation of methylmercury (IPCS, 1991). Be- mones at the 4 mg/m3 exposure concentration were attributed to
cause Hg2ϩ is highly reactive, it rapidly combines with intra- body weight loss and generalized toxicity. In the time-course
cellular ligands such as sulfhydryls, potentially disrupting en- study, rats were exposed to 2 mg/m3 Hg° or air beginning in
zymes and proteins essential to normal organ function.
metestrus and evaluated daily for 8 days. A lengthening of the
Although data on the reproductive toxicity of Hg° are lim- cycle was detected and morphological changes were observed in
ited, epidemiological studies have documented menstrual cycle the corpora lutea (CL) after exposure for 6 days. To determine if
abnormalities among women exposed to Hg° vapor. Six stud- changes in the CL and cyclicity correlated with a functional defect,
ies, conducted mostly in Europe, have reported menstrual cycle rats were exposed to Hg° vapor and evaluated for pregnancy
abnormalities (including changes in bleeding patterns and cy- outcome. There were no significant effects on pregnancy rate or
cle length) among women occupationally exposed to Hg° va- numbers of implantation sites when rats were exposed to 1 or 2
mg/m3 Hg° for 8 days prior to breeding, or when exposed for 8
por (De Rosis et al., 1985; Goncharuk, 1977; Marinova et al., days after breeding. These studies indicate that exposure to Hg°
1973; Mikhailova et al., 1971; Panova and Dimitrov, 1974; vapor altered estrous cyclicity, but had no significant effect on
Sikorski et al., 1987). In a more recent study, Rowland et al.
ovulation, implantation, or maintenance of first pregnancy during
(1994) found decreased fertility among female dental assistants exposure of short duration in female rats.
exposed to Hg° vapor. Women that prepared more than 30 Key Words: mercury vapor; menstrual cycle; female reproduc-
amalgams per week and who had poor occupational hygiene tive toxicity.
factors were only 63% as likely as unexposed women toconceive in any given menstrual cycle, whereas women whoprepared fewer than 30 amalgams per week or women who Elemental (metallic) mercury (Hg°) is a highly hazardous prepared more than 30 amalgams per week with the best chemical that can cause serious adverse health effects. Elemen- hygiene factors had better fecundability then even the unex- tal Hg° is the liquid form of mercury found in thermometers, posed women. These observations suggest the need to under- fluorescent light bulbs, barometers, blood pressure instruments, stand specific exposures of women and to understand how Hgmay affect the reproductive system.
Although the mechanism is not clear, all chemical forms of To whom correspondence should be addressed. Fax (919) 541-7666.
Hg administered to animals have been shown to result in reproductive problems such as spontaneous abortion, still- The functional breeding studies were separated into two study designs, referred births, congenital malformations, infertility, disturbances in the to as the Expose-Mate Study and the Mate-Expose Study. In the Expose-Matestudy, rats (n ϭ 6 –12) were exposed to air or 2 mg/m3 Hg° for a minimum of menstrual cycle, and inhibition of ovulation (for review: Bar- 8 days and then a control and Hg°-treated rat were paired with a male overnight low and Sullivan 1982; Schuurs, 1999). Most studies have been as exposure continued during the day. After sperm-positive smears were conducted with the inorganic forms of Hg and with systemic observed, exposure was discontinued and female rats were placed in holding toxicity and lethality often a reported outcome. The one study cages until necropsied 7 days after mating. The Mate-Expose study was of Hg° vapor that we are aware of reported that whole-body designed to distinguish effects on early implantation loss. Female rats werebred (n ϭ 6 per dose group) and then exposed to 0, 1, or 2 mg/m3 Hg° for 8 exposure to 2.5 mg/m3 Hg° for 6 h daily for 6 – 8 weeks caused days before necropsy. At necropsy, implantation sites and number of CL were a lengthening of the estrous cycle and postnatal pup mortality in treated female rats (Baranski and Szymczyk, 1973). How- Serum hormone analyses.
Rats were anesthetized by CO2 inhalation and ever, specific mechanisms of this reproductive toxicity were blood was collected by cardiac puncture. Serum was collected and stored at not identified. Moreover, 6 of 24 exposed rats died due to Hg –70° until analyzed for hormones. Estradiol and progesterone were measured poisoning, suggesting that the rats were systemically sick, by radioimmunoassay using commercially available kits from DiagnosticProducts, Inc. (Los Angeles, CA).
which in turn may have secondarily suppressed reproductive Histopathology.
Lungs, liver, right kidney, ovary, and uterus were col- activity including estrous cyclicity. Our studies described lected from treated and control rats at necropsy. Tissues were trimmed and herein investigate whether exposure to Hg° vapor at concen- fixed in 10% neutral-buffered formalin. Paraffin-embedded sections were trations that do not cause systemic toxicity can change endo- stained with hematoxylin and eosin and examined by light microscopy.
crine profiles over time and perturb the female reproductive Urine and tissue Hg analyses.
Urine was collected daily during each 2-h exposure. Individual animal urine volumes were recorded and then urine fromall exposed rats was pooled. Immediately after the last exposure, all rats wereeuthanized by CO2:O2 anesthesia followed by exsanguination. Brain, kidney, MATERIALS AND METHODS
liver, ovary and uterus were collected in acid-washed glass vials (prepared ina class 100 clean room) and stored at –20°C until analyzed. Tissue samples were weighed, homogenized, and digested overnight at 70°C in sealed vials.
After neutralization and dilution, samples were analyzed for total Hg by cold Generation and monitoring.
Hg° vapor was generated by passing condi- vapor atomic fluorescence spectrometry (Stockwell and Corns, 1993).
tioned air (HEPA filtered, charcoal-scrubbed, temperature and humidity con-trolled) through a flask containing elemental Hg (Aldrich Chemical Co., Statistical analyses.
Student’s t-test was used to determine statistically Milwaukee, WI). The resulting Hg° vapor was diluted and delivered to the significant differences between body weights, organ weights, hormone levels, exposure system at a controlled rate using mass flow controllers. Two nose- and tissue Hg levels in treated and control animals. Chi square analysis was only exposure systems (Lab Products, Rockville, MD) were used, one for used to determine estrous cycle differences (Sokal and Rohlf, 1969).
exposing control animals to conditioned air, and the other for exposing animalsto Hg° vapor. Each experiment consisted of one Hg° concentration group and a concurrent air-exposed control group. Air samples from the exposure systemwere analyzed every 15 min using a Jerome Model 431-X Mercury Analyzer Animals.
Female Sprague-Dawley rats (61– 67 days of age; Charles River Breeding Laboratories, Raleigh, NC) were housed three per cage. Feed (NIH- vapor for 7 and 11 days resulted in significant decreases in 07) and water (deionized, filtered tap water) were provided ad libitum except body weights relative to controls (Table 1). Body weights were during the 2-h exposures. During the 2 weeks prior to exposure, rats were not affected at exposure concentrations of 1 or 2 mg/m3.
acclimated to the exposure schedule by removing food and water each morningfor 2 h. Body weights were recorded daily.
Absolute and relative brain, kidney, liver, and uterus weights Estrous cyclicity.
Vaginal cytology was determined daily for each animal were not significantly changed by exposure to 1, 2, or 4 mg/m3 beginning 9 days before exposure and up to 11 days during Hg° exposure. The vaginal vaults were lavaged with sterile saline pH 7.4, and the aspirated lavage Total urinary Hg levels increased with in- fluid and cells were stained with Wright’s stain. Relative numbers of leuko- creasing exposure concentration and duration (Table 2). Uri- cytes, nucleated epithelial cells, and large squamous epithelial cells weredetermined and used to ascertain the estrous cycle stage (i.e., diestrus, nary Hg levels increased proportionately at the lower exposure proestrus, estrus, or metestrus). Cycle length was characterized as 4-day, concentrations. When examined at day 11, the urinary Hg 5-day, or greater than 5-day cycles. Rats with two consecutive 4-day cycles levels in the 2 mg/m3 group (53 ng/g) were about 2-fold greater were selected for study and then randomized by weight to treatment groups.
than in the 1 mg/m3 concentration group (19.1 ng/g). However, Animal exposures.
Animals were placed in cylindrical holding tubes urinary Hg levels in the 4 mg/m3 group (842 ng/g) were about during nose-only exposures. Preliminary experiments demonstrated that con- 16-fold greater than in the 2 mg/m3 group. Total Hg levels in finement of rats in holding tubes for longer than 2 h per day for up to 10 days(air exposure) resulted in significant reductions in body weight gain; for this urine of control rats were very low (0.44 ng/g).
reason, the exposures were limited to 2 h. In the dose-response study, rats were exposed for 11 days to 1 mg/m3 Hg° (n ϭ 9), 2 mg/m3 Hg° (n ϭ 15), or 4 kidney and brain Hg levels increased proportionately with Hg° mg/m3 Hg° (n ϭ 18), or conditioned air as controls (n ϭ 9, 15, or 18 per vapor exposure concentration (Table 3). Doubling the exposure comparison group, respectively). In the time-course study, rats (n ϭ 6 per timepoint per dose for a total of 48 control and 48 treated at 2 mg/m3 Hg° ) were concentration from 1 to 2 mg/m3 and from 2 to 4 mg/m3 exposed for 8 consecutive days beginning on metestrus or diestrus of the cycle.
resulted in 3-fold and 1.5-fold increases in kidney Hg levels, MERCURY VAPOR FEMALE REPRODUCTIVE TOXICITY Body Weights of Female Rats Exposed to Hg Vapor
Note. Rats were exposed to 4 mg/m3 Hg vapor 2 h/day for 7 and 11 days. Values represent means Ϯ SD (n).
aBody weights in grams.
bBody weight treated (g)/body weight of control (g) ϫ 100.
*Significantly less than controls (p Ͻ 0.05).
respectively. In the brain, doubling the exposure concentration exposure for 4 to 8 days; however, the biological significance from 1 to 2 mg/m3 resulted in a 2.3-fold increase, and from 2 of this change is unclear. Brain, kidney, lung, and uterus to 4 mg/m3 resulted in a 3.8-fold increase in Hg levels. Hg weights were unchanged relative to untreated controls (data not levels in kidney were 20- to 60-fold higher than levels mea- served in the corpora lutea of Hg-exposed rats that were vapor for 11 days had a greater percentage of estrous cycles necropsied at estrus or metestrus. The corpora lutea of exposed that were 5 days, or greater than 5 days (no cycle) compared to rats appeared immature compared to controls. Although mor- controls (Table 4). Exposure to 1 mg/m3 Hg° vapor had no phologically different, the number of corpora lutea were sim- significant effect on the estrous cycle.
ilar between exposed and control rats, and ovulation was confirmed in both groups by the presence of oocytes in the estradiol was decreased (17 Ϯ 2.1 pg/ml) compared to controls (33 Ϯ 9 pg/ml), and progesterone was increased (14 Ϯ 2.5 ng/ml) relative to controls (5.86 Ϯ 1.2 ng/ml). No significant prolonged after exposure for 6 to 8 days to 2 mg/m3 Hg° vapor.
changes in serum hormones were found in the other exposure The morphological changes in the corpora lutea (described groups relative to controls (data not shown).
content after exposure of rats to air or 2 mg/m3 Hg° vapor for up to 8 days (Table 5). Total Hg levels in ovaries of exposed sulted in a significant decrease in relative liver weights after rats were significantly increased over controls after the initial Total Hg Concentration in Urinea
Total Hg in Kidney and Brain of Rats Exposed to Hg° Vapor
Note. Urine was collected from rats immediately after the 2-h exposure to Hg° vapor or air (control). Urine from five rats/group was pooled and analyzed Note. Rats were exposed to Hg° vapor 2 h/day for 11 consecutive days.
for total Hg. The average Hg concentration in control urine was 0.44 ng/gm.
Immediately after the last exposure, rats were euthanized and tissues were aTotal Hg concentration in nanograms per gram urine.
collected and analyzed for total Hg. Values represent means Ϯ SD (n).
in laboratory animals (Schuurs, 1999); however, the mecha- Effect of Hg° Vapor Exposure on Estrous Cyclicity
nism(s) by which Hg° causes reproductive toxicity has not of Rats Exposed for 11 Days
been adequately addressed. In laboratory animal studies, ex-posure to relatively high concentrations of Hg° results in chem- ical-related effects such as weight loss or other secondary toxiceffects known to confound interpretation of reproductive stud- ies. A rat model of reproductive toxicity was used in these studies to investigate whether inhalation exposure to Hg° vaporcould perturb the female reproductive system at exposure con- Note. Female rats with two consecutive 4-day cycles were selected for this centrations that did not cause systemic toxicity.
study. Rats were exposed to Hg° vapor 2 h/day for 11 consecutive days andestrous cyclicity was determined by daily vaginal lavage. Cycle length was In addition to avoiding acute chemical-related effects, it was determined by the number of days between estrus smears. Data in table given also essential to minimize unnecessary stress to the rats caused as % rats. % rats determined by number of rats with specified cycle length/ by confinement during nose-only exposure. Preliminary studies with this rodent model established that nose-only exposure for *Significantly different from expected controls (p Ͻ 0.01).
greater than 2 h per day, even after acclimation, reduced bodyweight gain and altered estrous cyclicity in female rats (data exposure, and continued to increase during the 8-day study.
not presented). Consequently, rats were only exposed for 2 Total Hg levels in control ovaries were very low (0.003 ␮g/g).
h/day, which ultimately limited the dose of Hg but allowed the distinction between reproductive toxicity and systemic days had no significant effect on serum levels of estrogen and progesterone as shown by estrogen:progesterone ratios (Ta- Approximately 80% of inhaled Hg° is absorbed from the alveoli and distributed throughout the body (IPCS, 1991). Inorder to monitor the tissue dose of Hg under our exposure regimen, urine, kidney, and brain Hg levels were measured.
Relative to controls, there were no significant effects on Even though the exposure duration was limited to 2 h/day, mating efficiency, numbers of sperm positive females, numbers relatively high levels of Hg were attained in brain, kidney, and of corpora lutea and implantation sites, or hormone levels in urine. The kidney is the primary depository for Hg (IPCS, female rats exposed to 2 mg/m3 Hg° vapor for 8 days prior to 1991), and in this study Hg concentrations in kidney were 20- to 60-fold higher than those measured in the brain. Becausenephrotoxicity is an early symptom of Hg poisoning, the kid- ney was evaluated microscopically for evidence of tissue in- Relative to controls, there were no significant effects on jury. However, even at the high tissue Hg levels attained in this numbers of corpora lutea or implantation sites, or on hormone study, there was no histological evidence of toxicity in the levels in female rats that were first bred and then exposed to 2 kidney. Doubling the Hg° exposure concentration (1, 2, or 4 mg/m3 Hg° vapor for 8 days (Table 7).
mg/m3) resulted in proportionate increases in kidney and brainHg levels. However, the amount of Hg excreted in urine DISCUSSION
increased approximately 16-fold when the exposure concen-tration was doubled from 2 to 4 mg/m3. This nonlinear increase Exposure to relatively high Hg° vapor concentrations has in urinary Hg levels indicates a potential saturation of Hg been reported to cause reproductive dysfunction in women and uptake and storage at the 4 mg/m3 concentration level.
Estrogen:Progesterone Ratios and Total Hg in Ovaries of Rats Exposed to Hg° Vapor
Note. Beginning on metestrus (exposure day 1) all rats were exposed to either 2 mg/m3 Hg° vapor or air 2 h/day for 1 to 8 days. Letters in parentheses indicate expected cycle day (M ϭ metestrus, D ϭ diestrus, P ϭ proestrus, E ϭ estrus). Serum hormone estradiol to progesterone ratios and total Hg in the ovaries (␮g/gmtissue) were determined on various days of the estrous cycle. Values represent mean ratio of estradiol/progesterone Ϯ SEM. Values for total Hg in ovariesrepresent mean Ϯ SEM. The average total Hg in control ovaries ϭ 0.003 Ϯ 0.7 ␮g/g tissue.
MERCURY VAPOR FEMALE REPRODUCTIVE TOXICITY evaluated. Therefore, we reasoned that evaluation of pregnan- Expose-Mate Study
cies would assess the functionality of the corpora lutea and alsotest the integrity of the hypothalamus-pituitary-ovarian-uterine system. Two approaches were adopted. The first was to exposefemales to Hg° and then assess ovulation and mating efficiency (the number of mated females that became pregnant) by mea- suring sperm positivity, the number of CL (representing ovu- lations), and the number of implantations. If implantations were decreased, it would still be possible that Hg° affected theovary and/or the pup. Therefore, the second study design was Note. Female rats were exposed to air or 2 mg/m3 Hg° 2 h/day for 5 days, to mate the female, then expose to Hg° vapor to assess early and then were housed overnight with males as exposures continued during theday for up to 8 days. After sperm-positive smears were observed, exposure was implantation loss due to fetotoxicity separate from ovarian discontinued. Female rats were necropsied 9 days after mating was confirmed.
aNumber of sperm-positive females/number of females bred.
Under these conditions, no differences in mating efficiency, bNumber of pregnant females/number of sperm positive females.
c implantation numbers, or numbers of corpora lutea were found CL ϭ number of corpora lutea. Values represent means Ϯ SEM.
between control and Hg°-exposed rats. Thus, we conclude that Number of implantation sites. Values represent means Ϯ SEM.
eP/E ϭ progesterone/estrogen. Values represent means Ϯ SEM.
Hg° had no measurable effect on corpora luteal function in thisexposure scenario. Baranski and Szymczyk (1973) reported alengthening of the estrous cycle in Hg° vapor-exposed rats The dose-response studies indicated that exposure to 4 with no effect on mating efficiency; however, they observed a mg/m3 Hg° for 2 h/day was too toxic, causing significant body significant reduction in the number of implantations. The re- weight loss after only 7 days of exposure. In addition, the duced number of implantations was likely an indirect effect of nonlinear increase in urinary Hg output indicated that tissue Hg° toxicity, as the exposure duration was considerably longer uptake was saturated at this exposure concentration. For these in the Baranski and Szymczyk study (2.5 mg/m3 for 6 h/day, 5 reasons, the significant changes in estrous cycle and serum days/week for 21 days), and rats developed symptoms of Hg hormones observed at this high exposure concentration were poisoning (hyperactivity, chronic seizures, and whole body attributed to systemic toxicity and not due to a specific effect trembling) in the second and third weeks of exposure.
of Hg° on the reproductive system. However, alterations in The subtle changes in estrous cyclicity and corpora luteal estrous cyclicity without significant weight loss were observed morphology observed in the current study may indicate slight in the 2 mg/m3 Hg° vapor exposure group. Therefore, this perturbations in the feedback systems between the hypothala- exposure concentration was chosen to investigate the potential mus, pituitary, and ovary, as these alterations do not affect reproductive toxicity of Hg° vapor in a more sensitive time- steroid hormone levels or functional fertility. Hg has been shown to accumulate in the hypothalamus (Ernst et al., 1993) The time-course study similarly indicated that exposure to 2 and pituitary (Kosta et al., 1975) of rats exposed to Hg° vapor, mg/m3 Hg° slightly prolonged the estrous cycle and altered the and in the current study, high levels of Hg accumulated in the morphology of the corpora lutea; however, there were no ovaries of Hg°-exposed rats. The reaction of Hg with essential concomitant changes in serum estradiol or progesterone levels.
Prolongation of the estrous cycle (Lamperti and Printz, 1974)and morphological changes in corpora lutea with inhibition of follicular maturation (Lamperti and Printz, 1973) have been Mate-Expose Study
observed after injection of HgCl into female hamsters. Al- though estradiol and progesterone were not measured in thosestudies, follicle-stimulating hormone in the pituitary was re- portedly elevated (Lamperti and Niewenhuis, 1976).
Because the corpora lutea of cycling animals are not func- tional unless mating occurs, it was possible that Hg° could interfere with the ability of the corpora lutea to maintainprogesterone secretion and thereby maintain pregnancy, but Note. Female rats were housed overnight with males. After sperm-positive this adverse effect would not be detected in a cycling animal.
smears were observed, females were exposed to air or 2 mg/m3 Hg° for 8 days For this reason, it was difficult to interpret the functional significance of the subtle morphological changes in corpora Number of sperm-positive females/number of females bred.
bNumber of pregnant females/number of sperm positive females.
lutea. Two possibilities were that the corpora lutea were altered cCL ϭ number of corpora lutea. Values represent means Ϯ SEM.
due to Hg° vapor exposure, or that the changes were secondary dNumber of implantation sites. Values represent means Ϯ SEM.
and related to the time in the cycle that these rats were eP/E ϭ progesterone/estrogen. Values represent means Ϯ SEM.
intracellular proteins in these tissues could disrupt key feed- Chapin, R. E., Sloane, R. A., and Haseman, J. K. (1997). The relationships back systems involved in maintaining the timing or biological among reproductive endpoints in Swiss mice, using the reproductive assess-
ment by continuous breeding database. Fundam. Appl. Toxicol. 38, 129 –
clocks associated with estrous cyclicity.
These Hg° vapor inhalation studies were designed to inves- Cummings, A. (1993). Assessment of Implantation in the Rat. In Female tigate the mechanisms of Hg° vapor toxicity in the female rat Reproductive Toxicology, Methods in Toxicology (J. J. Heindel and R. E.
to support the epidemiological findings and to aid in the Chapin, Eds.), pp. 194 –198. Academic Press, San Diego, CA.
determination of public health risks. Our results demonstrate De Rosis, F., Anastasio, S. P., Selvaggi, L., Beltrame, A., and Moriani, G.
that Hg° vapor inhalation causes systemic toxicity, but does not (1985). Female reproductive health in two lamp factories: Effects of expo- cause ovarian or reproductive dysfunction within a short ex- sure to inorganic mercury vapour and stress factors. Brit. J. Ind. Med. 42,
posure period. It is possible that exposure to lower concentra- tions for longer exposure periods (weeks, months, or years) Ernst, E., Christensen, M. K., and Poulsen, E. H. (1993). Mercury in the rat hypothalamic arcuate nucleus and median eminence after mercury vapor would demonstrate a direct reproductive effect of Hg° vapor.
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This speculation is suggested by the finding that Hg° vapor Goncharuk, G. A. (1977). Problems relating to the occupational hygiene of exposure caused a slight estrous cycle lengthening in these women in production of mercury. Gig. Tr. Prof. Zabol. 5, 17–20.
short-term studies, and estrous cycle length is a useful marker Hayes. A. D., and Rothstein, A. (1962). The metabolism of inhaled mercury of overall reproductive function in evaluating reproductive vapor in the rat studied by isotope techniques. J. Pharmacol. Exp. Ther. 138,
toxicants in a continuous dosing and continuous breeding pro- tocol (Chapin et al., 1997). However, long-term studies with Kosta, L., Byrne, A. R., and Zekenko, V. (1975). Correlation between sele- nium and mercury in man following exposure to inorganic mercury. Nature Hg° are not feasible, given its highly toxic nature and the 254, 238 –239.
necessity to use nose-only exposures in our animal model.
Lamperti, A. A., and Printz, R. H. (1973). Effects of mercuric chloride on the Because of the complications and limitations of dosing, it is reproductive cycle of the female hamster. Biol. Reprod. 8, 378 –387.
equally difficult to directly compare exposure levels in our Lamperti, A. A., and Printz, R. H. (1974). Localization, accumulation, and acute studies in rats and exposure levels in occupationally toxic effects of mercuric chloride on the reproductive axis of the female exposed women. Women who exhibit apparent reproductive hamster. Biol. Reprod. 11, 180 –186.
problems due to occupational exposures have poor hygiene Lamperti, A. A., and Niewenhuis, R. (1976). The effects of mercury on the practices and/or exceed the time-weighted long-term threshold structure and function of the hypothalamo-pituitary axis in the hamster. Cell.
Tissue Res. 170, 315–324.
limit value of 10 ␮g/m3 Hg° in air (Schuurs, 1999). Given that Magos, L. (1967). Mercury blood interaction and mercury uptake by brain.
Hg is a highly hazardous chemical, we suggest that reproduc- Environ. Res. 1, 323–337.
tive effects noted in occupationally exposed women might be Marinova, G., Chakarova, O., and Kaneva, Y. A. (1973). A study of repro- secondary to systemic and/or neurotoxic effects of Hg, or ductive function of women working with mercury. Probl. Akush. Ginekol. 1,
perhaps symptomatic of exposures to multiple chemicals in the Mikhailova, L. M., Kobyets, G. P., Lyubomudrov, V. E., and Braga, G. F.
(1971). The influence of occupational factors on diseases of the female ACKNOWLEDGMENTS
reproductive organs. Pediatr. Akush. Ginekol. 33, 56 –58.
Panova, Z., and Dimitrov, G. (1974). The ovarian function in women with Inhalation exposures were conducted at the NIEHS inhalation facility under occupational exposure to metallic mercury. Akush. Ginekol. 13, 29 –34.
contract to ManTech Environmental Technology, Inc., Research Triangle Park, Rothstein, A., and Hayes. A. D. (1960). The metabolism of inhaled mercury in NC. Tissue Hg analyses were conducted by Research Triangle Institute, the rat studied by isotope techniques. J. Pharmacol. Exp. Ther. 138, 1–10.
Research Triangle Park, NC. The authors acknowledge the technical assistance Rowland, A. S. (1994). The effect of occupational exposure to mercury vapor of C. Colegrove, D. Crawford, P. Dixon, N. Gage, M. Goods, M. Moorman, S.
on the fertility of female dental assistants. Occup. Environ. Med. 51, 28 –34.
Philpot, P. Rydell, W. Stephens, and T. Ward.
Schuurs, A. H. B. (1999). Reproductive toxicity of occupational mercury. A review of the literature. J. Dentistry 27, 249 –256.
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