Timescales of developmental toxicity impacting on research and needs for intervention.

Much progress has happened in understanding developmental vulnerability to preventable environmental hazards. Along with the improved insight, the perspective has widened, and developmental toxicity now involves latent effects that can result in delayed adverse effects in adults or at old age and additional effects that can be transgenerationally transferred to future generations. Although epidemiology and toxicology to an increasing degree are exploring the adverse effects from developmental exposures in human beings, the improved documentation has resulted in little progress in protection, and few environmental chemicals are currently regulated to protect against developmental toxicity, whether it be neurotoxicity, endocrine disruption or other adverse outcome. The desire to obtain a high degree of certainty and verification of the evidence used for decision-making must be weighed against the costs and necessary duration of research, as well as the long-term costs to human health because of delayed protection of vulnerable early-life stages of human development and, possibly, future generations. Although two-generation toxicology tests may be useful for initial test purposes, other rapidly emerging tools need to be seriously considered from computational chemistry and metabolomics to CLARITY-BPA-type designs, big data and population record linkage approaches that will allow efficient generation of new insight; epigenetic mechanisms may necessitate a set of additional regulatory tests to reveal such effects. As reflected by the Prenatal Programming and Toxicity (PPTOX) VI conference, the current scientific understanding and the timescales involved require an intensified approach to protect against preventable adverse health effects that can harm the next generation and generations to come. While further research is needed, the main emphasis should be on research translation and timely public health intervention to avoid serious, irreversible and perhaps transgenerational harm.

Effect of hemoglobin adjustment on the precision of mercury concentrations in maternal and cord blood.

The cord-blood mercury concentration is usually considered the best biomarker in regard to developmental methylmercury neurotoxicity. However, the mercury concentration may be affected by the binding of methylmercury to hemoglobin and perhaps also selenium. As cord-blood mercury analyses appear to be less precise than suggested by laboratory quality data, we studied the interrelationships of mercury concentrations with hemoglobin in paired maternal and cord blood samples from a Faroese birth cohort (N=514) and the Mothers and Children's Environmental Health study in Korea (n=797). Linear regression and structural equation model (SEM) analyses were used to ascertain interrelationships between the exposure biomarkers and the possible impact of hemoglobin as well as selenium. Both methods showed a significant dependence of the cord-blood concentration on hemoglobin, also after adjustment for other exposure biomarkers. In the SEM, the cord blood measurement was a less imprecise indicator of the latent methylmercury exposure variable than other exposure biomarkers available, and the maternal hair concentration had the largest imprecision. Adjustment of mercury concentrations both in maternal and cord blood for hemoglobin improved their precision, while no significant effect of the selenium concentration in maternal blood was found. Adjustment of blood-mercury concentrations for hemoglobin is therefore recommended.

Negative confounding by essential fatty acids in methylmercury neurotoxicity associations.

BACKGROUND: Methylmercury, a worldwide contaminant of fish and seafood, can cause adverse effects on the developing nervous system. However, long-chain n-3 polyunsaturated fatty acids in seafood provide beneficial effects on brain development. Negative confounding will likely result in underestimation of both mercury toxicity and nutrient benefits unless mutual adjustment is included in the analysis. METHODS: We examined these associations in 176 Faroese children, in whom prenatal methylmercury exposure was assessed from mercury concentrations in cord blood and maternal hair. The relative concentrations of fatty acids were determined in cord serum phospholipids. Neuropsychological performance in verbal, motor, attention, spatial, and memory functions was assessed at 7 years of age. Multiple regression and structural equation models (SEMs) were carried out to determine the confounder-adjusted associations with methylmercury exposure. RESULTS: A short delay recall (in percent change) in the California Verbal Learning Test (CVLT) was associated with a doubling of cord blood methylmercury (-18.9, 95% confidence interval [CI]=-36.3, -1.51). The association became stronger after the inclusion of fatty acid concentrations in the analysis (-22.0, 95% confidence interval [CI]=-39.4, -4.62). In structural equation models, poorer memory function (corresponding to a lower score in the learning trials and short delay recall in CVLT) was associated with a doubling of prenatal exposure to methylmercury after the inclusion of fatty acid concentrations in the analysis (-1.94, 95% CI=-3.39, -0.49). CONCLUSIONS: Associations between prenatal exposure to methylmercury and neurobehavioral deficits in memory function at school age were strengthened after fatty acid adjustment, thus suggesting that n-3 fatty acids need to be included in analysis of similar studies to avoid underestimation of the associations with methylmercury exposure.

Visual evoked potentials in children prenatally exposed to methylmercury.

Prenatal exposure to methylmercury can cause both neurobehavioral deficits and neurophysiological changes. However, evidence of neurotoxic effects within the visual nervous system is inconsistent, possibly due to incomplete statistical adjustment for beneficial nutritional factors. We evaluated the effect of prenatal methylmercury exposure on visual evoked potential (VEP) latencies in Faroese children with elevated prenatal methylmercury exposure. A cohort of 182 singleton term births was assembled in the Faroe Islands during 1994-1995. At age 7 years, VEP tracings were obtained from 139 cohort subjects after exclusion of subjects with abnormal vision conditions. We used multiple regression analysis to evaluate the association of mercury concentrations in cord blood and maternal hair at parturition with VEP latencies after adjustment for potential confounders that included the cord-serum phospholipid concentration of n-3 polyunsaturated fatty acids (PUFAs) and the duration of breastfeeding. Unadjusted correlations between mercury exposure and VEP latencies were equivocal. Multiple regression models showed that increased mercury concentrations, especially in maternal hair, were associated with delayed latencies for VEP peak N145. After covariate adjustment, a delay of 2.22 ms (p=0.02) was seen for each doubling of the mercury concentration in maternal hair. In agreement with neuropsychological findings, the present study suggests that prenatal methylmercury exposure may have an adverse effect on VEP findings despite the absence of clinical toxicity to the visual system. However, this association was apparent only after adjustment for n-3 PUFA status.

Balancing the benefits of n-3 polyunsaturated fatty acids and the risks of methylmercury exposure from fish consumption.

Fish and shellfish are widely available foods that provide important nutrients, particularly n-3 polyunsaturated fatty acids (n-3 PUFAs), to many populations globally. These nutrients, especially docosahexaenoic acid, confer benefits to brain and visual system development in infants and reduce risks of certain forms of heart disease in adults. However, fish and shellfish can also be a major source of methylmercury (MeHg), a known neurotoxicant that is particularly harmful to fetal brain development. This review documents the latest knowledge on the risks and benefits of seafood consumption for perinatal development of infants. It is possible to choose fish species that are both high in n-3 PUFAs and low in MeHg. A framework for providing dietary advice for women of childbearing age on how to maximize the dietary intake of n-3 PUFAs while minimizing MeHg exposures is suggested.

Selenium as a potential protective factor against mercury developmental neurotoxicity.

Experimental studies suggest that selenium (Se) may decrease methylmercury (MeHg) toxicity under certain exposure regimens. In epidemiological studies, the exposure to MeHg occurs from fish and seafood, which are also a source of beneficial nutrients such as selenium. However, little is known about the potential protective effects of dietary Se against MeHg neurotoxicity in humans. The possible interaction was assessed in two birth cohorts in the Faroe Islands, consisting of singleton term births from 1986 to 1987 (N=1,022), and 1994 to 1995 (N=182), respectively. Dietary habits in this fishing population included frequent consumption of seafood, including whale meat high in mercury. Both Hg and Se were measured in cord whole blood. Neurodevelopmental outcomes were evaluated at age 7 years in both cohorts, and the smaller cohort also included neurological assessment on several prior occasions. Each outcome was modeled as a function of Hg and Se interactions (with adjustments for potential risk factors) by expressing the effects of log10(Hg) within the lowest 25%, the middle 50%, and the highest 25% of the Se distribution. Surplus Se was present in cord blood, the average being a 10-fold molar excess above MeHg. Regression analyses failed to show consistent effects of Se, or statistically significant interaction terms between Se and MeHg. Overall, no evidence was found that Se was an important protective factor against MeHg neurotoxicity. Prevention, therefore, needs to address MeHg exposures rather than Se intakes. Because of the benefits associated with fish intake during pregnancy, consumers should be advised to maintain a high fish and seafood intake that is low in Hg contamination. Additional research is needed to determine the identity of the nutrients responsible for the beneficial effects.