Lawrence J. Fischer

Human Exposure to Mercury: A Critical Assessment of the Evidence of Adverse Health Effects

The ubiquitous nature of mercury in the environment, its global atmospheric cycling, and its toxicity to humans at levels that are uncomfortably close to exposures experienced by a proportion of the population are some of the current concerns associated with this pollutant. The purpose of this review is to critically evaluate the scientific quality of published reports involving human exposures to mercury and associated health outcomes as an aid in the risk evaluation of this chemical. A comprehensive review of the scientific literature involving human exposures to mercury was performed and each publication evaluated using a defined set of criteria that are considered standards in epidemiologic and toxicologic research. Severe, sometimes fatal, effects of mercury exposure at high levels were primarily reported as case studies. The disasters in Minamata, Japan, in the 1950s and in Iraq in 1971-1972 clearly demonstrated neurologic effects associated with ingestion of methylmercury both in adults and in infants exposed in utero. The effects were convincingly associated with methylmercury ingestion, despite limitations of the study design. Several well-conducted studies have investigated the effects of methylmercury at levels below those in the Iraq incident but have not provided clear evidence of an effect. The lower end of the dose-response curve constructed from the Iraq data therefore still needs to be confirmed. The studies of mercury exposure in the workplace were mainly of elemental or inorganic mercury, and effects that were observed at relatively low exposure levels were primarily neurologic and renal. Several studies have investigated effects associated with dental amalgam but have been rated as inconclusive because of methodologic deficiencies. In our overall evaluation, 29 of 110 occupational studies and 20 of 54 studies where exposure occurred in the natural environment provided at least suggestive evidence of an exposure-related effect.

Maternal fish consumption, mercury levels, and risk of preterm delivery.

Background Pregnant women receive mixed messages about fish consumption in pregnancy because unsaturated fatty acids and protein in fish are thought to be beneficial, but contaminants such as methylmercury may pose a hazard. Methods In the Pregnancy Outcomes and Community Health (POUCH) study, women were enrolled in the 15th to 27th week of pregnancy from 52 prenatal clinics in five Michigan communities. At enrollment, information was gathered on amount and category of fish consumed during the current pregnancy, and a hair sample was obtained. A segment of hair closest to the scalp, approximating exposure during pregnancy, was assessed for total mercury levels (70–90% methylmercury) in 1,024 POUCH cohort women. Results Mercury levels ranged from 0.01 to 2.50 μg/g (mean = 0.29 μg/g; median = 0.23 μg/g). Total fish consumption and consumption of canned fish, bought fish, and sport-caught fish were positively associated with mercury levels in hair. The greatest fish source for mercury exposure appeared to be canned fish. Compared with women delivering at term, women who delivered before 35 weeks’ gestation were more likely to have hair mercury levels at or above the 90th percentile (≥ 0.55 μg/g), even after adjusting for maternal characteristics and fish consumption (adjusted odds ratio = 3.0; 95% confidence interval, 1.3–6.7). Conclusion This is the first large, community-based study to examine risk of very preterm birth in relation to mercury levels among women with low to moderate exposure. Additional studies are needed to see whether these findings will be replicated in other settings.

Examination of the immunosuppressive effect of Δ9-tetrahydrocannabinol in streptozotocin-induced autoimmune diabetes☆

delta9-Tetrahydrocannabinol (delta9-THC) is capable of modulating a variety of immune responses, but has not been evaluated in models of immune-based diabetes. The objectives of the present study were: (a) to investigate the effect of delta9-THC in an established model of multiple low dose streptozotocin (MLDSTZ)-induced autoimmune diabetes; and (b) to determine the contribution of the immune response in the MLDSTZ model. CD-1 mice were treated with 40 mg/kg STZ for 5 days in the presence or absence of delta9-THC treatment. delta9-THC administered orally in corn oil at 150 mg/kg for 11 days attenuated, in a transient manner, the MLDSTZ-induced elevation in serum glucose and loss of pancreatic insulin. MLDSTZ-induced insulitis and increases in IFN-gamma, TNFalpha and IL-12 mRNA expression were all reduced on Day 11 by co-administration of delta9-THC. In separate studies, six doses of delta9-THC, given after completion of STZ treatment, was found equally effective in attenuating mice from MLDSTZ-induced diabetes. Studies performed using B6C3F1 mice showed moderate hyperglycemia and a significant reduction in pancreatic insulin by MLDSTZ in the absence of insulitis. In addition, MLDSTZ produced a less pronounced hyperglycemia compared to CD-1 mice that was not attenuated by delta9-THC. These results suggest that MLDSTZ can initiate direct beta-cell damage, thereby augmenting the destruction of beta-cells by the immune system. Moreover, these results indicate that delta9-THC is capable of attenuating the severity of the autoimmune response in this experimental model of autoimmune diabetes.

Fish Consumption and Other Characteristics of Reproductive-Aged Michigan Anglers—a Potential Population for Studying the Effects of Consumption of Great Lakes Fish On Reproductive Health

There has been considerable interest in the benefits and risks of eating Great Lakes fish, particularly with regard to reproductive health. We report the results of a survey conducted from 1993-1995 among Michigan anglers. The survey was designed to identify a reproductive-aged cohort of persons who consume high or low levels of Great Lakes fish in order to study the impact of polyhalogenated biphenyl (PHB) compounds and other toxins on human reproduction outcomes. Using fishing license data obtained from the Michigan Department of Natural Resources, we identified anglers of early reproductive age (18-34 years) in ten Michigan counties. The screening survey ascertained demographic, behavioral, fish consumption, and reproductive history information on anglers and their partners. Over 4,000 angler households were contacted. One thousand nine hundred fifty questionnaires were returned from 1,168 households. The median age of respondents was 30 years; 58% were male and 64% reported being married. Slightly more than one-half the respondents had attended or graduated from college, and less than 10% had not completed high school. In the past year, most respondents (46%) reported having eaten sport-caught fish 1-12 times, while 20% reported having eaten no sport-caught fish; 20% had consumed 13-24 meals. More sport-caught fish was consumed in the spring and summer than in the fall and winter, and males reported eating more fish than females. About 43% of our respondents reported that they intend to have one or more children in the next five years. Of these respondents, 287 couples had no identified impairments to reproduction and therefore would be eligible to participate in the future reproductive study.

Cyproheptadine-induced alterations in clonal insulin-producing cell lines.

Cyproheptadine (CPH) inhibits glucose-stimulated insulin synthesis and secretion, and reversibly depletes pancreatic insulin content in the rat. To examine whether the inhibitory actions of CPH on insulin cell function are linked to the ability of glucose to stimulate insulin synthesis and secretion, studies were performed in two different insulin-producing cell lines. CPH effects were compared in HIT-T15 cells, which respond to glucose with increased insulin synthesis and secretion, and in glucose-unresponsive RINm5F cells. CPH produced similar alterations in both cells lines. After a 48-hr culture period in the presence of 0, 0.1, 1.0 or 10.0 microM CPH, cellular insulin stores and media insulin levels were decreased in a concentration-dependent manner. At 10.0 microM CPH, RIN and HIT cell insulin content declined to 34 and 33% of controls respectively. Cellular insulin returned to control levels 48 hr after removal of CPH. In experiments designed to test a direct inhibitory effect on stimulated insulin secretion, 1 and 10.0 microM concentrations of CPH were found to inhibit glucose-stimulated insulin release from HIT cells, and K+, alanine and glyceraldehyde-stimulated release from RIN cells. CPH was also shown to inhibit insulin biosynthesis in both cell lines at concentrations that did not alter the synthesis of total cellular proteins. All of these alterations in cellular function were shown to occur at CPH concentrations that did not affect cell growth or viability. The results show that the actions of CPH do not appear to be dependent upon the existence of operational glucose signalling mechanisms for insulin synthesis and secretion.

Age-related susceptibility to the insulin-depleting action of 4-diphenylmethylpiperidine in young rats

Studies were undertaken to investigate age-related changes in the ability of 4-diphenylmethylpiperidine (4-DPMP) to reduce levels of pancreatic insulin in young rats. Oral doses of 4-DPMP (5.0 or 10.0 mg/kg) were given once daily for two days to 9-, 15- and 21-day-old rats. Twenty-four hours after the last dose, pancreatic insulin content, non-fasting serum glucose, and the amount of unchanged 4-DPMP present in the whole body were estimated. 4-DPMP treatment produced a decline in pancreatic insulin and the extent of this action was greater in younger animals. The observed changes in pancreatic insulin were not reflected in altered serum glucose levels, showing this parameter is a relatively poor indicator of pancreatic insulin loss. Younger animals had a larger fraction of the total dose of 4-DPMP in the body at the end of the experimental period when compared to the fraction retained by older rats. The age-related susceptibility of young rats to the diabetogenic action of 4-DPMP may be related to the differences in the rate of elimination of the chemical at different ages.