Potential developmental neurotoxicity of pesticides used in Europe

Pesticides used in agriculture are designed to protect crops against unwanted species, such as weeds, insects, and fungus. Many compounds target the nervous system of insect pests. Because of the similarity in brain biochemistry, such pesticides may also be neurotoxic to humans. Concerns have been raised that the developing brain may be particularly vulnerable to adverse effects of neurotoxic pesticides. Current requirements for safety testing do not include developmental neurotoxicity. We therefore undertook a systematic evaluation of published evidence on neurotoxicity of pesticides in current use, with specific emphasis on risks during early development. Epidemiologic studies show associations with neurodevelopmental deficits, but mainly deal with mixed exposures to pesticides. Laboratory experimental studies using model compounds suggest that many pesticides currently used in Europe – including organophosphates, carbamates, pyrethroids, ethylenebisdithiocarbamates, and chlorophenoxy herbicides – can cause neurodevelopmental toxicity. Adverse effects on brain development can be severe and irreversible. Prevention should therefore be a public health priority. The occurrence of residues in food and other types of human exposures should be prevented with regard to the pesticide groups that are known to be neurotoxic. For other substances, given their widespread use and the unique vulnerability of the developing brain, the general lack of data on developmental neurotoxicity calls for investment in targeted research. While awaiting more definite evidence, existing uncertainties should be considered in light of the need for precautionary action to protect brain development

The ethics of human volunteer studies involving experimental exposure to pesticides: unanswered dilemmas

The controversy about the use of data from human volunteer studies involving experimental exposure to pesticides as part of regulatory risk assessment has been widely discussed, but the complex and interrelated scientific and ethical issues remain largely unresolved. This discussion paper, generated by authors who comprised a workgroup of the ICOH Scientific Committee on Rural Health, reviews the use of human experimental studies in regulatory risk assessment for pesticides with a view to advancing the debate as to when, if ever, such studies might be ethically justifiable. The discussion is based on three elements: (a) a review of discussion papers on the topic of human testing of pesticides and the positions adopted by regulatory agencies in developed countries; (b) an analysis of published and unpublished studies involving human testing with pesticides, both in the peer-reviewed literature and in the JMPR database; and (c) application of an ethical analysis to the problem. The paper identifies areas of agreement which include general principles that may provide a starting point on which to base criteria for judgements as to the ethical acceptability of such studies. However, the paper also highlights ongoing unresolved differences of opinion inherent in ethical analysis of contentious issues, which we propose should form a starting point for further debate and the development of guidelines to achieve better resolution of this matter.<br/

Coherent somatic mutation in autoimmune disease.

Many aspects of autoimmune disease are not well understood, including the specificities of autoimmune targets, and patterns of co-morbidity and cross-heritability across diseases. Prior work has provided evidence that somatic mutation caused by gene conversion and deletion at segmentally duplicated loci is relevant to several diseases. Simple tandem repeat (STR) sequence is highly mutable, both somatically and in the germ-line, and somatic STR mutations are observed under inflammation.Protein-coding genes spanning STRs having markers of mutability, including germ-line variability, high total length, repeat count and/or repeat similarity, are evaluated in the context of autoimmunity. For the initiation of autoimmune disease, antigens whose autoantibodies are the first observed in a disease, termed primary autoantigens, are informative. Three primary autoantigens, thyroid peroxidase (TPO), phogrin (PTPRN2) and filaggrin (FLG), include STRs that are among the eleven longest STRs spanned by protein-coding genes. This association of primary autoantigens with long STR sequence is highly significant (p<3.0x10(-7)). Long STRs occur within twenty genes that are associated with sixteen common autoimmune diseases and atherosclerosis. The repeat within the TTC34 gene is an outlier in terms of length and a link with systemic lupus erythematosus is proposed.The results support the hypothesis that many autoimmune diseases are triggered by immune responses to proteins whose DNA sequence mutates somatically in a coherent, consistent fashion. Other autoimmune diseases may be caused by coherent somatic mutations in immune cells. The coherent somatic mutation hypothesis has the potential to be a comprehensive explanation for the initiation of many autoimmune diseases