Scientific Issues Relevant to Setting Regulatory Criteria to Identify Endocrine Disrupting Substances in the European Union

Background: Endocrine disruptors (EDs) are defined by the World Health Organization (WHO) as exogenous compounds or mixtures that alter function(s) of the endocrine system and consequently cause adverse effects in an intact organism, or its progeny, or (sub)populations. European regulations on pesticides, biocides, cosmetics, and industrial chemicals require the European Commission to establish scientific criteria to define EDs. Objectives: We address the scientific relevance of four options for the identification of EDs proposed by the European Commission. Discussion: Option 1, which does not define EDs and leads to using interim criteria unrelated to the WHO definition of EDs, is not relevant. Options 2 and 3 rely on the WHO definition of EDs, which is widely accepted by the scientific community, with option 3 introducing additional categories based on the strength of evidence (suspected EDs and endocrine-active substances). Option 4 adds potency to the WHO definition, as a decision criterion. We argue that potency is dependent on the adverse effect considered and is scientifically ambiguous, and note that potency is not used as a criterion to define other particularly hazardous substances such as carcinogens and reproductive toxicants. The use of potency requires a context that goes beyond hazard identification and corresponds to risk characterization, in which potency (or, more relevantly, the dose–response function) is combined with exposure levels. Conclusions: There is scientific agreement regarding the adequacy of the WHO definition of EDs. The potency concept is not relevant to the identification of particularly serious hazards such as EDs. As is common practice for carcinogens, mutagens, and reproductive toxicants, a multi-level classification of ED based on the WHO definition, and not considering potency, would be relevant (corresponding to option 3 proposed by the European Commission). Citation: Slama R, Bourguignon JP, Demeneix B, Ivell R, Panzica G, Kortenkamp A, Zoeller RT. 2016. Scientific issues relevant to setting regulatory criteria to identify endocrine disrupting substances in the European Union. Environ Health Perspect 124:1497–1503; http://dx.doi. org/10.1289/EHP21

Chlorination Disinfection By-Products in Drinking Water and Congenital Anomalies: Review and Meta-Analyses

This study aims to review epidemiologic evidence of the association between exposure to chlorination disinfection by-products (DBPs) and congenital anomalies. All epidemiologic studies that evaluated a relationship between an index of DBP exposure and risk of congenital anomalies were analyzed. For all congenital anomalies combined, the meta-analysis gave a statistically significant excess risk for high versus low exposure to water chlorination or TTHM (17%; 95% CI, 3-34) based on a small number of studies. The meta-analysis also suggested a statistically significant excess risk for ventricular septal defects (58%; 95% CI, 21-107), but based on only three studies, and there was little evidence of an exposure-response relationship. It was observed no statistically significant relationships in the other meta-analyses and little evidence for publication bias, except for urinary tract defects and cleft lip and palate. Although some individual studies have suggested an association between chlorination disinfection by-products and congenital anomalies, meta-analyses of all currently available studies demonstrate little evidence of such association

Identification and Description of the Uncertainty, Variability, Bias and Influence in Quantitative Structure-Activity Relationships (QSARs) for Toxicity Prediction

Improving regulatory confidence in, and acceptance of, a prediction of toxicity from a quantitative structure-activity relationship (QSAR) requires assessment of its uncertainty and determination of whether the uncertainty is acceptable. Thus, it is crucial to identify potential uncertainties fundamental to QSAR predictions. Based on expert review, sources of uncertainties, variabilities and biases, as well as areas of influence in QSARs for toxicity prediction were established. These were grouped into three thematic areas: uncertainties, variabilities, potential biases and influences associated with 1) the creation of the QSAR, 2) the description of the QSAR, and 3) the application of the QSAR, also showing barriers for their use. Each thematic area was divided into a total of 13 main areas of concern with 49 assessment criteria covering all aspects of QSAR development, documentation and use. Two case studies were undertaken on different types of QSARs that demonstrated the applicability of the assessment criteria to identify potential weaknesses in the use of a QSAR for a specific purpose such that they may be addressed and mitigation strategies can be proposed, as well as enabling an informed decision on the adequacy of the model in the considered context

Long-term consequences of arsenic poisoning during infancy due to contaminated milk powder

Arsenic toxicity is a global health problem affecting many millions of people. The main source of exposure is drinking water contaminated by natural geological sources. Current risk assessment is based on the recognized carcinogenicity of arsenic, but neurotoxic risks have been overlooked. In 1955, an outbreak of arsenic poisoning occurred among Japanese infants, with more than 100 deaths. The source was contaminated milk powder produced by the Morinaga company. Detailed accounts of the Morinaga dried milk poisoning were published in Japanese only, and an overview of this poisoning incident and its long-term consequences is therefore presented. From analyses available, the arsenic concentration in milk made from the Morinaga milk powder is calculated to be about 4–7 mg/L, corresponding to daily doses slightly above 500 μg/kg body weight. Lower exposures would result from using diluted milk. Clinical poisoning cases occurred after a few weeks of exposure, with a total dose of about 60 mg. This experience provides clear-cut evidence for hazard assessment of the developmental neurotoxicity. At the present time, more than 600 surviving victims, now in their 50s, have been reported to suffer from severe sequelae, such as mental retardation, neurological diseases, and other disabilities. Along with more recent epidemiological studies of children with environmental arsenic exposures, the data amply demonstrate the need to consider neurotoxicity as a key concern in risk assessment of inorganic arsenic exposure

Contamination of rural surface and ground water by endosulfan in farming areas of the Western Cape, South Africa

BACKGROUND: In South Africa there is little data on environmental pollution of rural water sources by agrochemicals. METHODS: This study investigated pesticide contamination of ground and surface water in three intensive agricultural areas in the Western Cape: the Hex River Valley, Grabouw and Piketberg. Monitoring for endosulfan and chlorpyrifos at low levels was conducted as well as screening for other pesticides. RESULTS: The quantification limit for endosulfan was 0.1 μg/L. Endosulfan was found to be widespread in ground water, surface water and drinking water. The contamination was mostly at low levels, but regularly exceeded the European Drinking Water Standard of 0.1 μg/L. The two most contaminated sites were a sub-surface drain in the Hex River Valley and a dam in Grabouw, with 0.83 ± 1.0 μg/L (n = 21) and 3.16 ± 3.5 μg/L (n = 13) average endosulfan levels respectively. Other pesticides including chlorpyrifos, azinphos-methyl, fenarimol, iprodione, deltamethrin, penconazole and prothiofos were detected. Endosulfan was most frequently detected in Grabouw (69%) followed by Hex River (46%) and Piketberg (39%). Detections were more frequent in surface water (47%) than in groundwater (32%) and coincided with irrigation, and to a lesser extent, to spraying and trigger rains. Total dietary endosulfan intake calculated from levels found in drinking water did not exceed the Joint WHO/FAO Meeting on Pesticide Residues (JMPR) criteria. CONCLUSION: The study has shown the need for monitoring of pesticide contamination in surface and groundwater, and the development of drinking water quality standards for specific pesticides in South Africa

Scientific Opinion on the safety and efficacy of vitamin D₃ (cholecalciferol) as a feed additive for all animal species or categories based on a dossier submitted by Lohmann Animal Health GmbH

The principal physiological role of vitamin D in all vertebrates is in calcium and phosphorus homeostasis. The classic clinical deficiency syndrome is rickets. The FEEDAP Panel notes that for turkeys for fattening, equines, bovines, ovines and pigs the maximum authorised content of vitamin D3 in feed does not provide any margin of safety, and that, except for pigs and fish, the maximum content is above the upper safe level, according to National Research Council data when animals were fed a supplemented diet for more than 60 days. The FEEDAP Panel is not in a position to draw final conclusions on the safety of vitamin D for target animals but considers the current maximum contents temporarily acceptable pending a review of the recent scientific literature. The two vitamin sources under application are considered safe for the target animals provided the current maximum contents in feed are respected. Any administration of vitamin D3 via water for drinking could exceed the safe amounts of vitamin D and therefore represents a safety concern. Current nutritional surveys in 14 European countries showed that vitamin D intake is below the upper safe limit. The FEEDAP Panel assumes that foodstuffs of animal origin were produced following current production practices, including vitamin D3 supplementation of feed, and concludes that the use of vitamin D in animal nutrition at the currently authorised maximum dietary content has not and will not cause the tolerable upper intake level to be exceeded. Vitamin D3 should be considered as irritant to skin and eyes, and as a dermal sensitiser. Inhaled vitamin D3 is highly toxic; exposure to dust is harmful. No environmental risk resulting from the use of vitamin D3 in animal nutrition is expected. The vitamin D3 under application is regarded as an effective dietary source of the vitamin in animal nutrition