Toxicology and Industrial Health

The subchronic inhalation toxicity of a methanol/gasoline blend (85% methanol, 15% gasoline, v/v) was studied in rats. Sprague Dawley rats (10 animals per group) of both sexes were exposed to vapors of methanol/gasoline at 50/3, 500/30 and 5000/300 ppm for 6 hours per day, 5 days per week, for 13 weeks. Control animals inhaled filtered room air only. Control recovery and high dose recovery groups were also included which inhaled room air for an extra 4 weeks following the treatment period. No clinical signs of toxicity were observed in the treatment group and their growth curves were not significantly different from the control. Except for decreased forelimb grip strength in the high dose females, no treatment-related neurobehavioural effects (4-6 hours post inhalation) were observed using screening tests which included cage-side observations, righting reflex, open field activities, and forelimb and hindlimb grip strength. At necropsy, the organ to body weight ratios for the liver, kidneys, spleen, testes, thymus and lungs were not significantly different from the control group. There were no treatment-related effects in the hematological endpoints and no elevation in serum formate levels. Minimal serum biochemical changes were observed with the only treatment-related change being the decreased creatinine in the females. A dose-related increase in urinary ascorbic acid was detected in males after 2,4 and 8 weeks of exposure, but not after the 12th week, and in females only at week-2. Increased urinary albumin was observed in treated males starting at the lowest dose and at all exposure periods, but not in females. A treatment-related increase in urinary β ₂-microglobulin was detected in males at week-2 only. Except for mild to moderate mucous cell metaplasia in nasal septum B, which occurred more often and with a slightly higher degree of severity in the low dose groups of both sexes, and presence of a minimal degree of interstitial lymphocyte infiltration in the prostate glands of the high dose males, no other significant microscopic changes were observed in the tissues of treated animals. Based on the marked increase in urinary ascorbic acid and albumin in the high dose males and the decreased forelimb grip strength in the high dose females, we concluded that the no-observed adverse effect level (NOAEL) of methanol/gasoline vapor is 500/30 ppm.

Chloroacetonitrile (CAN), a drinking water disinfectant by-product, has mutagenic and carcinogenic properties. CAN is known to deplete glutathione (GSH), and previous studies reported an enhanced molecular interaction of CAN after GSH depletion in the uterine and fetal tissues of mice. The present report may help to understand the potential mechanisms involved in such molecular interactions by examining the disposition, transplacental uptake and covalent interaction of the chemical in normal and GSH depleted pregnant mice (at 13^th day of gestation). Both normal and GSH depleted (by administration of Diethylmaleate (DEM), 0.6 mL/kg, i.p.) pregnant mice were given an equitoxic i.v. dose of 2-[¹⁴C]-CAN (333 μCi/kg equivalent to 77 mg/kg). Animals were processed for whole-body autoradiography (WBA) at 1, 8 and 24 hr after treatment. Tissue distribution of radioactivity in the autoradiographs was quantitated using computer aided image analysis. With few exceptions, a rapid high uptake (at I hr) of radioactivity was observed in all major maternal (liver, lung, urinary bladder, gastrointestinal mucosa, cerebellum, uterine luminal fluid) and fetal (liver, brain) organs of both normal and GSH depleted mice. This pattern of distribution was observed, with lesser intensity, at 8 hr following treatment. At a later time period (24 hr), there was a significant higher retention and covalent interaction of radioactivity in GSH depleted mouse tissues especially in the liver as compared to normal mouse. This study suggests that 2-[¹⁴C]-CAN and/or its metabolites are capable of crossing the placental barrier. The observed higher uptake and retention of the radioactivity in the maternal liver, kidney, cerebellum, nasal turbinates and fetal liver may pose toxicity of the chemical to these organs. The increased covalent interaction of radioactivity in GSH depleted mice liver may indicate the potential utilization of GSH pathway by this organ in the detoxication of CAN derived metabolites and thus exerting hepatotoxicity.

Objective: To determine the effect of iron deficiency anemia on blood and tissue lead distribution.Methods: 24 weanling rats were divided into 2 groups. One group received an iron replete diet (200 ppm); the other received a low iron diet (20 ppm). After 24 days, each group was further subdivided into two doses of lead (5 mg/kg and 10 mg/kg) which was administered intravenously. Rats were continued on their respective diets for 7 days post-lead injection to allow tissue distribtrtion, then sacrificed and blood and tissue lead concentration measured. Results: Prior to lead administration, baseline blood lead concentrations were not significantly different between groups. At sacrifice, whole blood lead levels were significantly higher in iron deficient animals than in iron replete at both 5 and 10 mg/kg administered lead. Iron deficient animals had comparable lead concentrations to iron replete animals in brain, kidney and liver. Femur lead concentrations were higher at 10 mg/kg administered lead. Conclusion: Iron deficiency alters lead distribution such that increased lead is found in blood for a given exposure.

The advances in medical technology during the last four decades has provided evidence for an underlying neurological basis for autism. The etiology for the variations of neurofunctional anomalies found in the autistic spectrum behaviors appears inconclusive as of this date but growing evidence supports the proposal that chronic exposure to toxic agents, i.e., xenobiotic agents, to a developing central nervous system may be the best model for defining the physiological and behavioral data found in these populations. A total of 20 subjects (15 males and 5 females) who received a formal diagnosis of autism by a developmental pediatrician, pediatric neurologist, or licensed psychologist were included.. The mean age for the sample was 635 yrs (range = 3-12 years). This study employed several measures that collectively would provide evidence of burden levels of xenobiotic agents and abnormal liver detoxication processes. These included: (1) Glucaric Acid Analysis, (2) blood analyses for identification of specific xenobiotic agents, and (3) Comprehensive Liver Detoxification Evaluation. Kolmogorov-Smirnov testing for a chi-square and Normal distribution for the Glucaric Acid findings indicates that each of these distributions is significantly different from expected distributions (p <.01). It is most noteworthy that of the 20 cases examined for this study, 100% of the cases showed liver detoxication profiles outside of normal. An examination of 18 autistic children in blood analyses that were available showed that 16 of these children showed evidence of levels of toxic chemicals exceeding adult maximum tolerance. In the two cases where toxic chemical levels were not found, there was abnormal D-glucaric acid findings suggesting abnormal xenobiotic influences on liver detoxication processes. A proposed mechanism for the interaction of xenobiotic toxins with immune system dysfunction and continuous and/or progressive endogenous toxicity is presented as it relates to the development of behaviors found in the autistic spectrum.