Octamethylcyclotetrasiloxane (D4) is a highly volatile cyclic siloxane used to produce silicone polymers. D4 has been shown to attenuate the LH surge in rats, resulting in reduced litter sizes. However, it has been hypothesized that these biological effects observed only at high dose levels of D4 may be because of changes in membrane microviscosity (fluidity) leading to a non-specific mode of action. Here, we set out to determine if D4 increases membrane microviscosity and link this to membrane domain function alterations. The studies reported here support the hypothesis that D4 affects ovulation via a concentration-dependent, physical-chemical mode of action that is not specific for any particular component of the neuro-endocrine system and is, therefore, not endocrine disruption but a non-specific effect. Furthermore, D4 also increases the membrane fluidity of the hypothalamic cell membrane in vitro. It is expected that a similar response would occur in vivo. This alteration in membrane fluidity decreases the release of GnRH and kisspeptin. GnRH and kisspeptin are necessary for the pre-ovulatory LH surge from the pituitary. In the absence of a GnRH and kisspeptin release, there is no signal to the pituitary for the driver of the LH surge. D4 can change membrane fluidity in vitro and likely in vivo and associated behaviors of membrane proteins/lipoproteins of various kinds via non-specific mechanisms.

To investigate the potential toxicity of Octamethylcyclotetrasiloxane (D4), studies in laboratory rats have used primarily one of two strains, Sprague-Dawley (SD) and Fischer-344 (F-344). Reproductive studies used SD rats whereas F-344 rats were used in D4 pharmacokinetics, metabolism, acute/subacute/chronic toxicity and oncogenicity studies. Here, we assessed specific endpoints related to D4 pharmacokinetics and biochemistry in SD and F-344 rats within a single study, which allows for direct comparisons between strain and sex. This assessment included determination of microsomal total P450, NADPH-cytochrome c reductase, epoxide hydrolase, CYP2B1/2, CYP1A1/2, CYP3A1/2, CYP2C11, and CYP2A1. Aside from slight brown pigment in the liver, the treated animals experienced no toxicologically significant weight loss, decrease in food consumption, or clinical signs. Concentrations of D4 in plasma and fat were generally greater in females relative to males in both strains. SD females appeared to have statistically significantly greater plasma and fat concentrations following 28 days of repeated exposure to D4 relative to F-344 rats, suggesting the existence of potential sex and strain differences in D4 pharmacokinetics. The effect of D4 exposure on liver enzyme expression was similar among and between sexes and strain and was consistent with that for phenobarbital-like inducers. Notable differences included a finding of elevated CYP2B1/2 protein levels without a similar magnitude of increase in CYP2B/1 activity and a greater degree of CYP3A1/2 induction (protein and activity) for female SD rats. The importance of these findings is unclear, however reduced CYP2B1/2 activity may give rise to lower rates of D4 metabolism and clearance, consistent with the higher tissue levels of D4 in SD relative to F-344 female rats.

Octamethylcyclotetrasiloxane (D4) has been shown to have effects on the female rat reproductive cycle. This study evaluated the phase of the female rat reproductive cycle affected by D4 using a study design that allowed the complete female reproductive cycle, as well as phases of the cycle, from pre-mating through gestation, to be evaluated. Rats were exposed via whole body vapor inhalation up to 700ppm D4 during the overall phase (28 days prior to mating through gestation day (GD) 19), the ovarian phase (31–3 days prior to mating), the fertilization phase (3 days prior to the start of mating through gestation day 3), and the implantation phase (GD 2–GD 5) of the reproductive cycle. D4 was associated with decreases in implantation sites and litter size in the overall and fertilization phases, but not in the ovarian or implantation phases. In order to further define the sensitive period for D4 exposure, additional groups of rats were exposed on single days. A single 6h exposure to D4 on the day prior to mating resulted in a significant reduction in fertility. These data indicate that there is a very narrow window, around the time of ovulation and fertilization, for D4 to exert effects on the reproductive cycle of the female rat. Subsequent research, reported elsewhere, has elucidated the mode of action and assessed its potential relevance to humans.

This study evaluated the potential toxicity of whole-body vapor inhalation of octamethylcyclotetrasiloxane (D4) on reproductive capabilities in exposed F0 and F1 parental animals and the potential effects on neonatal survival, growth, and development of the F1 and F2 offspring. F0 male and female Sprague–Dawley rats (30/sex/group) were exposed to D4 vapor at concentrations of 0, 70, 300, 500 or 700 ppm 6 h per day for at least 70 consecutive days prior to mating and lasted through weaning of the pups on postnatal day (PND) 21. Female exposures were suspended from gestation day (GD) 21 through PND 4 to allow for parturition and permit continuous maternal care for the early neonates. Starting on PND 22, F1 weanlings were exposed to D4 as described for the F0 generation. The F2 pups were not directly exposed to D4. F0 animals were mated once to produce the F1 generation; F1 parental animals were mated twice to produce two F2 litters. In addition, the F1 males were mated with unexposed females. Prolonged estrous cycles, decreased mating and fertility indices were observed in the F1 generation exposed to D4 for the first and second matings. Significant reductions in the mean number of pups born and mean live litter size were observed in the 500 and 700 ppm groups for both the F0 and F1 generations. Implantation sites were also reduced at 700 ppm for both F0 and F1 generations. No adverse effects were observed at any exposure level on anogenital distance, vaginal patency and preputial separation. No adverse effects were seen on male functional reproductive parameters, spermatogenic endpoints, microscopic evaluation of male reproductive tissue, or when the D4-exposed F1 males were mated with the unexposed females, demonstrating that the reproductive toxicity observed was due to D4 exposure to the females. Based on the lack of effect on reproduction when the D4-exposed males were mated to näive females, the NOAEL for male reproductive toxicity was considered to be 700 ppm. Based on the statistically significant effects on fertility and litter size, NOAEL for female reproductive toxicity was considered to be 300 ppm. The findings observed in this study are consistent with suppression or delaying of LH surge as well as acceleration of the onset of female reproductive senescence in the rat. While analogous pathways control ovulation in both rats and humans, there are significant differences in the mechanism for timing and release of LH and resulting changes in the control of ovulation and mating behavior between the two species. If D4 delays rather than causes a prolonged suppression or ablation of the LH surge, the reproductive mode of action of D4 would not likely be relevant for humans.

The objectives of this study were to assess the potential for D4 to suppress the pre-ovulatory lutenizing hormone (LH) surge, to block or delay ovulation, and to evaluate potential effects on reproductive hormones in rats. Female Sprague–Dawley Crl:CD® (SD) IGS BR rats received whole-body vapor inhalation exposure to D4 (0, 700, or 900 ppm) 6 h per day for 3 days. Trunk blood obtained on proestrus at 10 a.m. was evaluated for levels of follicle stimulating hormone (FSH), estradiol (E2), estrone (E1), and progesterone (P4). Other rats had serial blood samples collected via cannula at 2, 4, 6, 8, and 10 p.m. on the day of proestrus and plasma evaluated for LH and prolactin (PRL). Trunk blood was collected at 8 a.m. of estrus and plasma evaluated for FSH, E2, E1, and P4. At 10 a.m. on proestrus, significant increases in E1 levels in the 700 and 900 ppm groups and significant increases in P4 levels in the 900 ppm group were noted. At 8 a.m. on estrus, significant increases in E1, E2, in the E1/E2 ratio and decreases in FSH were noted in the 700 and 900 ppm groups. The major effect on the LH profile was observed most clearly when the rats were grouped by ovulatory status, animals that did or did not ovulate. Regardless of treatment, suppression of the LH surge correlated with blocked ovulation. The percentage of rats that ovulated was (700 ppm, 42%; 900 ppm, 31%) compared to controls (79%). Overall, the data indicate that high exposures to D4 attenuated the pre-ovulatory LH surge and significantly decreased the portion of female rats that ovulated.

This two-generation reproduction study assessed the reproductive hazard potential of decamethylcyclopentasiloxane (D5). Sprague–Dawley rats (30/sex/group) were exposed by whole-body vapor inhalation to a target concentration of 30, 70, or 160 ppm D5 or filtered air for 6 h/day. Exposures for the F0 and F1 generations started at least 70 days prior to mating and lasted through weaning of the respective pups on postnatal day (PND) 21. Female exposures were interrupted from gestation day (GD) 21 through PND 4 to allow for parturition and to permit continuous maternal care for the early neonates. F2 pups were not directly exposed to D5. There were no exposure-related mortalities, clinical signs of toxicity, or effects on body weight or food consumption. There were no treatment-related gross findings or organ weight effects at the F0 and F1 necropsies. Other than minimal alveolar histiocytosis in all exposed groups, there were no noteworthy microscopic findings. Reproductive parameters (number of days between pairing and mating, mating and fertility indices, gestation length, and parturition), spermatogenic parameters and ovarian primordial follicle counts and numbers of corpora lutea in the F0 and F1 parental animals were not significantly changed between treated and control groups. Mean live litter sizes, number of pups born, sex ratios, pup body weights, postnatal pup survival and general physical condition of offspring in each generation were not affected. The slight, but statistically significant, increase in the mean F1 male pup AGD in the 160 ppm group was not considered to be related to treatment. Vaginal patency and balanopreputial separation were unchanged compared to controls. Thus, the No-Observed-Adverse-Effect-Level (NOAEL) for parental and reproductive toxicity was determined to be 160 ppm D5.

The acute inhalation toxicity of 10 chlorosilanes was investigated in Fischer 344 rats using a 1-h whole-body vapor inhalation exposure and a 14-day recovery period. The median lethal concentration (LC50(1)) for each material was calculated from the nominal exposure concentrations and mortality. Experimentally derived LC50(1) values for monochlorosilanes (4257-4478 ppm) were greater than those for dichlorosilanes (1785-2092 ppm), which were greater than those for trichlorosilanes (1257-1611 ppm). Apparent was a strong structure-activity relationship (r2 = .97) between chlorine content and LC50(1) value. Estimated LC50(1) values for mono-, di-, and trichlorosilanes were determined to be 3262, 1639, and 1066 ppm, respectively, utilizing this relationship and the lower limit of the 95% prediction interval. The LC50(1) values determined in this series of studies were greater than that reported for hydrogen chloride (3124 ppm), when expressed on a chlorine equivalence basis (3570-5248 ppm), demonstrating that the acute toxicity of these chlorosilanes is similar to or less than that for hydrogen chloride. The good correlation between chlorine content and LC50(1) provides a sound basis for estimation of LC50(1) for chlorosilanes not already evaluated. The use of structure-activity relationships is consistent with the chemical industry and federal agency initiatives to reduce, refine, and/or replace the use of animals in testing without compromising the quality of health and safety assessments.

LetterOpen AccessBioavailability of D4 after inhalation and implantation exposure to silicones. Robert G Meeks Robert G Meeks Published:1 August 2002https://doi.org/10.1289/ehp.110-a442Cited by:2AboutSectionsPDF ToolsDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InReddit FiguresReferencesRelatedDetailsCited By Johnson W, Bergfeld W, Belsito D, Hill R, Klaassen C, Liebler D, Marks J, Shank R, Slaga T, Snyder P and Andersen F (2012) Safety Assessment of Cyclomethicone, Cyclotetrasiloxane, Cyclopentasiloxane, Cyclohexasiloxane, and Cycloheptasiloxane, International Journal of Toxicology, 10.1177/1091581811428184, 30:6_suppl, (149S-227S), Online publication date: 1-Dec-2011. Lee D, Ahn C, An B and Jeung E (2015) Induction of the Estrogenic Marker Calbindn-D9k by Octamethylcyclotetrasiloxane, International Journal of Environmental Research and Public Health, 10.3390/ijerph121114610, 12:11, (14610-14625) Vol. 110, No. 8 August 2002Metrics About Article Metrics Publication History Originally published1 August 2002Published in print1 August 2002 Financial disclosuresPDF download License information EHP is an open-access journal published with support from the National Institute of Environmental Health Sciences, National Institutes of Health. All content is public domain unless otherwise noted. Note to readers with disabilities EHP strives to ensure that all journal content is accessible to all readers. However, some figures and Supplemental Material published in EHP articles may not conform to 508 standards due to the complexity of the information being presented. If you need assistance accessing journal content, please contact [email protected]. Our staff will work with you to assess and meet your accessibility needs within 3 working days.

Octamethylcyclotetrasiloxane (D4) is a low-molecular-weight cyclic siloxane used primarily in the synthesis of silicone polymers. The objective of the present study was to evaluate the subchronic toxicity of D4 following a 3-month nose-only inhalation exposure. Male and female Fischer 344 rats (20/sex/group) were exposed 6 h/day, 5 days/week for 3 months to vapor concentrations of 0, 35, 122, 488, and 898 ppm D4. Also, an additional 10 per sex in the control and high-exposure groups were allowed a 4-week recovery period to observe reversibility, persistence, or delayed occurrence of any potential adverse effects. Body weights and food consumption were monitored at least twice weekly over the course of exposures. Approximately 18 hours preceding euthanasia, animals were transferred into metabolism cages for urine collection, and were fasted. At necropsy, rats were anesthetized with pentobarbital and euthanized by exsanguination. Blood was collected for hematological and clinical biochemical analyses. Selected organ weights were measured and a complete set of tissues was taken for histopathological examination. A concentration-dependent increase in absolute and relative liver weight (488 to 898 ppm) and a significant decrease in ovarian weight (898 ppm) were observed in female rats. Exposure to D4 via nose-only inhalation (35 to 898 ppm) produced minor alterations in hematological and serum chemistry parameters that were considered either incidental and of little toxicological significance (hematology) or suggestive of metabolic adaptation/alteration (serum chemistry) in response to exposure-related hepatomegaly. There were no histopathological findings noted in the liver. Histopathological evidence indicated the primary target organs following D4 inhalation exposure to be components of the female reproductive tract. Reversible histopathological changes were observed in the ovary (hypoactivity) and vagina (mucification) of female rats in the high-dose group only (898 ppm). Although an increase in the incidence and severity of both macrophage accumulation, interstitial inflammation, and eosinophil infiltration was observed in the lungs of male and female rats exposed to D4, the toxicological significance is uncertain as other inhalation studies at similar concentrations failed to show these effects. In summary, nose-only inhalation of a high concentration of D4 resulted in reversible histopathological changes in the female rat reproductive tract. Lower concentrations did not elicit these same effects.

Hexamethyldisiloxane (HMDS) is a volatile linear siloxane dimer used in many applications, including precision cleaning, active ingredient carrier, and as a manufacturing intermediate. The purpose of this study was to characterize the subchronic vapor inhalation toxicity of the material as part of a comprehensive toxicology program. Groups of 20 male and 20 female Fischer 344 (F344) rats were exposed to nominal (and mean actual) vapor concentrations of 0, 50 (50), 200 (194), 600 (593), 1,500 (1,509) and 5,000 (5,012) ppm of HMDS, 6 hours per day, 5 days per week, for 13 weeks. No treatment-related signs of clinical toxicity or mortality, statistically significant effects upon body weight gain or food consumption, ophthalmoscopic changes, gross macroscopic necropsy findings, or organ weight changes were noted. Minor hematological, clinical biochemical, and urinalysis changes were seen but were not considered to be of toxicological relevance. Histological lesions in the kidney apparently consistent with male rat-specific alpha-2-urinary globulin nephropathy were observed in male rats exposed to 593, 1,509, and 5,012 ppm of HMDS, accompanied by slightly increased plasma urea and creatinine concentrations. No other treatment-related histological changes were seen in HMDS-exposed rats.

Octamethylcyclotetrasiloxane (D4) has been described as a phenobarbital-like inducer of hepatic enzymes. Phenobarbital (PB) and phenobarbital-like chemicals induce transient hepatic and thyroid hyperplasia and sustained hypertrophy in rats and mice. The extent to which these processes are involved with D4-induced hepatomegaly is not known. The present study has evaluated the effects of repeated inhalation exposure to D4 vapors on hepatic and thyroid cell proliferation and hypertrophy with respect to time and exposure concentration. Female Fischer 344 rats were exposed via whole body inhalation to 0 ppm D4, 700 ppm D4 vapors (6 h/day; 5 days/week), or 0.05% PB in drinking water over a 4-week period. Incorporation of 5′-bromo-2-deoxyuridine (BrdU) and the abundance of proliferating cell nuclear antigen were used as indicators of cell proliferation. Designated animals from each treatment group were euthanized on study days 6, 13, and 27. The effect of D4 exposure concentration on hepatic cell proliferation was evaluated at 0, 7, 30, 70, 150, 300, or 700 ppm. Liver-to-body weight ratios in animals exposed to 700 ppm D4 were increased 18, 20, and 22% over controls while PB-treated animals showed increases of 33, 27, and 27% over controls on days 6, 13, and 27 respectively. Hepatic incorporation of BrdU following exposure to D4 was highest on day 6 (labeling index = 15–22%) and was at or below control values by day 27. This pattern of transient hyperplasia was observed in all hepatic lobes examined and was similar to the pattern observed following treatment with PB.

The cyclic siloxane octamethylcyclotetrasiloxane (D4) and the linear siloxane hexamethyldisiloxane (HMDS) have numerous industrial and consumer applications and thus have the potential for human exposure. The present study was undertaken to examine potential estrogenic and antiestrogenic activities of D4 and HMDS. To address potential differences in sensitivity between rat strains the study used both Sprague-Dawley (SD) and Fischer 344 (F-344) rats. Estrogenicity of the test compounds was determined by measuring absolute and relative uterine weights in immature rats and by monitoring uterine epithelial cell height. In order to place the data obtained for D4 into perspective relative to strong and weak estrogenic compounds, the response produced by D4 at 0, 10, 50, 100, 250, 500, and 1000 mg/kg/day was compared to responses produced by ethinyl estradiol (EE) (1, 3, 10, or 30 microg/kg/day), diethylstilbestrol dipropionate (DES-DP) (0.5, 1.5, 5, 15 microg/kg/day), and coumestrol (CE) (10, 35, 75, 150 mg/kg/day). Antiestrogenic effects were evaluated by co-administering D4 (500 mg/kg/day) with EE at 1, 3, 10, and 30 microg /kg/day. All compounds were administered in sesame oil at a volume of 5 mL/kg by oral gavage. Beginning on postnatal day 18 (SD) or 21 (F-344) each pup (12 per group) received a single dose of test compound once a day for 4 consecutive days. The pups were euthanized the morning after the last treatment and their uteri removed, weighed, and processed for histological examination. EE and DES-DP produced a significant dose-dependent increase in absolute and relative uterine weights and uterine cell height. The maximum increase in uterine weight following EE exposure was approximately 350% relative to controls in both strains. The weak phytoestrogen CE also produced a dose-related increase in absolute and relative uterine weight and epithelial cell height, but the response occurred over a much higher range of doses. At the highest dose of CE, uterine weight was increased approximately 230% relative to controls. Following exposure to D4, absolute and relative uterine weights and uterine epithelial cell height were statistically significantly increased in both strains of rats at doses above 100 mg/kg/day. In terms of uterine weight, D4 was approximately 0.6 million times less potent than EE or DES-DP in SD pups and 3.8 million times less potent than EE or DES-DP in F-344 pups. The maximal increase in uterine weight, relative to controls, produced by D4 at 1000 mg/kg/day was approximately 160% in SD rats, while the maximum increase produced by D4 in F-344 rats was 86%. D4 co-administered over a wide range of EE doses, resulted in a significant reduction in uterine weight compared to EE alone. HMDS was evaluated in SD rats only. The response produced by HMDS (600 and 1200 mg/kg/day) was compared to EE (3 microg/kg/day). Antiestrogenic effects were evaluated by co-administering HMDS (1200 mg/kg/day) with EE at 3 microg/kg/day. HMDS had no measurable effect on uterine weight under the experimental conditions described here. However, HMDS coadministered with EE did produce a small, but statistically significant reduction in uterine weight compared to EE alone. In conclusion, D4 showed weak estrogenic and antiestrogenic activity that was several orders of magnitude less potent than EE, and many times less potent than the weak phytoestrogen CE.

The retention, distribution, metabolism, and excretion of [(14)C]octamethylcyclotetrasiloxane (D(4)) were studied in Fischer 344 rats after single and multiple exposures to 7, 70, or 700 ppm [(14)C]D(4). Subset groups were established for body burden, distribution, and elimination. Retention of inhaled D(4) was relatively low (5-6% of inhaled D(4)). Radioactivity derived from [(14)C]D(4) inhalation was widely distributed to tissues of the rat. Maximum concentrations of radioactivity in plasma and tissues (except fat) occurred at the end of exposure and up to 3 h postexposure. Maximum concentrations of radioactivity in fat occurred as late as 24 h postexposure. Fat was a depot, elimination of radioactivity from this tissue was much slower than from plasma and other tissues. With minor exceptions, there were no consistent gender effects on the distribution of radioactivity and the concentrations of radioactivity were nearly proportional to exposure concentration over the exposure range. Excretion of radioactivity was via exhaled breath and urine, and, to a much lesser extent, feces. Urinary metabolites included dimethylsilanediol and methylsilanetriol plus five minor metabolites. Relative abundance of these metabolites was the same from every test group. Elimination was rapid during the first 24 h after exposure and was slower thereafter (measured up to 168 h postexposure). In singly-exposed female (but not male) rats, small dose-dependent shifts in elimination pathways were seen. After multiple exposures, the elimination pathways were dose- and gender-independent. These data define possible pathways for metabolism of D(4) and allow estimation of the persistence of D(4) and/or its metabolites in rats.

Repeated inhalation exposure to octamethylcyclotetrasiloxane (D4) produces a reversible and dose-related hepatomegaly and proliferation of hepatic endoplasmic reticulum in rats. However, the effects of D4 on the expression of cytochrome P450 enzymes have not been evaluated. In the present study, the time course for changes in hepatic microsomal cytochrome P450 enzyme expression following repeated inhalation exposure to D4 vapors was determined in male and female Fischer 344 rats. Animals were exposed to D4 vapor at concentrations of 70 and 700 ppm, via whole body inhalation for 6 h/day, 5 days/week for 4 weeks. Specified animals were euthanized on exposure days 3, 7, 14, 21, and 28. Microsomal fractions were prepared from fresh liver by differential centrifugation. Enzyme activity as well as immunoreactive protein levels of several cytochrome P450 enzymes (CYP), epoxide hydrolase, and UDP-glucuronosyltransferase (UDPGT) were evaluated. The time course for enzyme induction was monitored by measuring 7-ethoxyresorufin O-deethylase (EROD) and 7-pentoxyresorufin O-depentylase (PROD) activities on days 3, 7, 14, 21, and 28. CYP1A1/2 activity, as determined by EROD activity, was increased approximately 2- to 3-fold over the exposure period. However, an examination of immunoreactive protein revealed no induction of CYP1A1 and a suppression of CYP1A2 in the 700 ppm D4 group. In comparison, CYP2B1/2 enzyme activity, as determined by PROD, was significantly increased as early as day 3 in both the 70 and 700 ppm D4 groups of male and female rats. Overall, PROD activity on day 28 was induced more than 10-fold in the 70 ppm D4 groups and more than 20-fold in the 700 ppm D4 groups. The increase in PROD activity was paralleled by a comparable increase in CYP2B1/2 immunoreactive protein. There was a modest (2- to 3-fold) increase in CYP3A1/2 activity and immunoreactive protein, as determined by 6 beta-hydroxylation of testosterone and Western blot analysis. Expression of CYP enzymes was at or near maximum by day 14 and remained relatively constant throughout the exposure period. On day 28, epoxide hydrolase activity and immunoreactive protein were induced (2- to 3-fold) in a dose-dependent manner. Only slight changes in the expression and activity of UDPGT were detected, and these did not appear to be dose related. Thus, repeated inhalation exposure to D4 induces CYP enzymes and epoxide hydrolase in a manner similar to that observed for phenobarbital (PB). Therefore, D4 can be described as a "PB-like" inducer of hepatic microsomal enzymes in the Fischer 344 rat.

D5 is a low-molecular-weight cyclic siloxane used for industrial and consumer product applications. The objective of the present study was to evaluate the subchronic toxicity of D5 following a 3-month nose-only inhalation exposure. In addition, animals from both sexes of the control and high dose groups were allowed a 4-week recovery period to observe reversibility, persistence, or delayed occurrence of any potential adverse effects. Male and female Fischer 344 rats were exposed for 6 h/day, 5 days/week for 3 months to target concentrations of 0 (30/sex/group), 26 (20/sex/group), 46 (20/sex/group), 86 (20/sex/group), and 224 (30/sex/group) ppm D5. Recovery groups (0 and 224 ppm) comprised 10 rats/sex/group. Body weights and food consumption were monitored at least twice weekly over the course of exposures. Approximately 16 h preceding euthanasia, animals were transferred into metabolism caging for urine collection and were fasted. Rats were anesthetized with pentobarbital and euthanized by exsanguination. Blood was collected for hematological and clinical biochemical analyses. Selected organ weights were measured and a complete set of tissues was taken for histopathological examination. There were several minor changes observed in clinical biochemistry parameters; the most notable was an increase in gamma glutamyl transferase (gamma-GT) in both sexes at the high dose. In females, this effect was dose-related (46-224 ppm) and did not recover upon cessation of exposure. Additionally, there was an decrease in serum lactate dehydrogenase (LDH) observed in females at 86 and 224 ppm which was not resolved during recovery. There was an increase in absolute and/or relative liver weight in rats of both sexes. Taken together, these data suggest that the female rat is more sensitive to the actions of D5 on the liver. Exposure-related increases in absolute and relative lung weights were observed in both sexes at terminal necropsy. This observation was not noted in males in the recovery phase, but was still present in females. Finally, histopathological evidence indicated the primary target organ following D5 inhalation exposure is the lung, with an increase in focal macrophage accumulation and interstitial inflammation in the lungs of male and female rats exposed to 224 ppm D5. This observation did not appear to resolve at the end of a 1-month period of nonexposure. The incidence of these changes was also slightly increased in rats of both sexes exposed to 86 ppm D5. These data suggest that nose-only D5 vapor inhalation provokes minimal changes in the lung which are similar in incidence and severity to spontaneously occurring changes in control animals after nose-only exposures. There were no histopathological findings noted in the livers which support this organ as a target in this study, despite the observed changes in organ weight and in some serum chemistry parameters.

Studies reported here assessed the potential adverse effects of silicone gel, Dow Corning Q7-2159A, on general reproduction and fetal development in male and female Charles River CD rats and New Zealand white rabbits. Two control and three treatment groups of 30 male and 30 female rats and 25 female rabbits per group were used in the one-generation reproduction and developmental toxicity studies, respectively. The silicone gel was implanted subcutaneously in two flank sites at dosage levels of 3, 10, and 30 ml/kg. The highest dose was selected on the basis of likely human body burden. Control groups received either sterile saline or carboxymethylcellulose solution in two flank implantation sites. The control and test articles were implanted in male and female rats 61 and 47 days, respectively, prior to mating (in the rat reproduction study) and approximately 42 days prior to insemination of female rabbits (in the rabbit developmental toxicity study). There were no treatment-related effects on F0 parental general conditions and reproductive performance, F1 neonatal viability, or growth in the rat reproduction study. No maternal nor developmental effects, including teratogenicity, were observed in rabbits in the groups implanted with Q7-2159A gel in the developmental toxicity study.

We postulated that patients with hereditary hemochromatosis (HH) absorb increased quantities of lead, as do iron-deficient subjects. To test this hypothesis, whole blood lead concentration ([blood Pb]) was quantified by atomic absorption spectrometry in HH homozygotes (n = 44), obligate heterozygotes (n = 19), normal control subjects (n = 33), and abnormal controls, with transfusion-induced iron overload (n = 8). HH homozygotes had higher [blood Pb] than did normal control subjects (5.6 +/- 0.6 microgram/dl vs 3.6 +/- 0.5 microgram/dl; p < 0.005); significantly increased mean [blood Pb] was observed in both male and female homozygotes. In heterozygotes, the mean [blood Pb] 4.1 +/- 0.5 microgram/dl) was intermediate between that of homozygotes and normal control subjects. The mean [blood Pb] of subjects with transfusion-induced iron overload (22 +/- 0.6 microgram/dl) did not differ significantly from that of normal controls. The findings in homozygotes could to be related to age, serum ferritin concentration, presence or absence of iron loading, or the extent of therapeutic phlebotomy. Lead exposure in all of our subjects was due primarily to ambient sources. Analysis of our data, when using a mathematical biokinetic model of human lead metabolism, suggests that the most likely explanation for our findings is that homozygotes (and, to a lesser extent, heterozygotes) absorb increased quantities of lead, a conclusion that corresponds to the increased absorption of iron and cobalt previously documented in homozygotes.