Manuela Tiramani

Neurobehavioral Effects of Pesticides: State of the Art

The authors have reviewed the literature on neurobehavioral toxicity of pesticides to assess the status of knowledge on this matter. Some data suggest that exposure to DDT and fumigants may be associated with permanent decline in neurobehavioral functioning and increase in psychiatric symptoms, but, due to the limited number of studies available and the scarce knowledge on exposure levels, no firm conclusion can be drawn. Data on subjects acutely poisoned with organophosphorous compounds suggest that an impairment in neurobehavioral performance and, in some cases, emotional status may be observed as a long-term sequela, but the possibility still remains that these effects were only an aspecific expression of damage and not of direct neurotoxicity. Studies carried out on subjects chronically exposed to organophosphates, but never acutely poisoned, do not provide univocal results but the slight changes consistently observed in sheep dippers suggest the need of focusing on activities characterized by relatively higher exposure levels. In general, the main limits of existing knowledge are the variability of the testing methods used, which makes it difficult to compare the results of single studies, and the scarce knowledge on exposure levels. A promising approach may be the conduction of prospective longitudinal or cohort studies, where exposure and dose assessment can be more easily controlled, or the evaluation of cohorts of workers a priori selected for the availability of environmental and biological monitoring data. The follow up of the populations under study may give an answer at the problem of the prognostic significance of the observed changes. Also the protocols used to assess neurobehavioral functioning need to be standardized.

International STakeholder NETwork (ISTNET): creating a developmental neurotoxicity (DNT) testing road map for regulatory purposes

Abstract A major problem in developmental neurotoxicity (DNT) risk assessment is the lack of toxicological hazard information for most compounds. Therefore, new approaches are being considered to provide adequate experimental data that allow regulatory decisions. This process requires a matching of regulatory needs on the one hand and the opportunities provided by new test systems and methods on the other hand. Alignment of academically and industrially driven assay development with regulatory needs in the field of DNT is a core mission of the International STakeholder NETwork (ISTNET) in DNT testing. The first meeting of ISTNET was held in Zurich on 23–24 January 2014 in order to explore the concept of adverse outcome pathway (AOP) to practical DNT testing. AOPs were considered promising tools to promote test systems development according to regulatory needs. Moreover, the AOP concept was identified as an important guiding principle to assemble predictive integrated testing strategies (ITSs) for DNT. The recommendations on a road map towards AOP-based DNT testing is considered a stepwise approach, operating initially with incomplete AOPs for compound grouping, and focussing on key events of neurodevelopment. Next steps to be considered in follow-up activities are the use of case studies to further apply the AOP concept in regulatory DNT testing, making use of AOP intersections (common key events) for economic development of screening assays, and addressing the transition from qualitative descriptions to quantitative network modelling.

Ethylenethiourea in urine as an indicator of exposure to mancozeb in vineyard workers

In the present study, the personal exposure to mancozeb and/or ethilenethiourea (ETU) in 13 Italian vineyard workers and in 13 subjects without occupational exposure to pesticides was investigated. With this aim, the level of ETU in urine and the dermal exposure to mancozeb were determined. Baseline urinary ETU results were lower than the analytical limit of detection for all controls (<0.5 microg/g creatinine) and for ten workers (median <0.5, range <0.5-3.4 microg/g creatinine). In workers, urinary ETU was significantly increased at the end of shift (2.5, <0.5-95.2 microg/g creatinine) compared with baseline levels. End-shift urinary ETU was higher in operators using open tractors (n=7) than in those using closed tractors (n=5) (16.2 vs. 2.4 microg/g creatinine), but the difference was not significant (P=0.073). End-shift urinary ETU was positively correlated with dermal exposure to mancozeb determined both over the clothes and on the skin (Spearmans rho=0.770 and 0.702, P=0.009 and 0.024, respectively). Wine consumption positively influenced the excretion of ETU.

Neurobehavioural effects of pesticides with special focus on organophosphorus compounds: which is the real size of the problem?

The risk of neurobehavioural impairment as a consequence of a prolonged, low dose exposure to neurotoxic pesticides is not clearly demonstrated despite numerous publications addressing the topic. We reviewed the 24 papers published on human neurobehavioural effects of organophosphorus and/or carbamates pesticides up to May 1st 2008. Variables evaluated were compound/s addressed, number of subjects, approach to measure or estimate exposure, characteristics of control groups and presence of confounders, methodological approach, and type of alteration, taking into account cognitive, sensory-motor, psychological, and psychomotor measures. A total of 6 papers considered the whole spectrum of functions, the studies yielding positive or uncertain results were 13 (68%) for cognitive function, 11 (69%) for psychomotor function, 11 (65%) for sensory-motor function, and 11 (65%) for psychological function impairment. In 46% of the positive studies a previous severe acute poisoning was reported. Exposure levels were measured only in 5 studies, and very often there were problems in the selection of controls, and firm conclusions on the risk of neurobehavioural effects cannot be reached yet. The main limits of the available data are: limited number of studies and compounds addressed, significant differences in the approach among studies, poor concordance of the results of different studies, and difficulties in controlling confounding factors. Nevertheless, there are sufficient data to conclude that neurobehavioural impairment might be the consequence of an acute poisoning, and possibly the consequence of relatively high and prolonged exposures.

Glyphosate toxicity and carcinogenicity: a review of the scientific basis of the European Union assessment and its differences with IARC

Glyphosate is the most widely used herbicide worldwide. It is a broad spectrum herbicide and its agricultural uses increased considerably after the development of glyphosate-resistant genetically modified (GM) varieties. Since glyphosate was introduced in 1974, all regulatory assessments have established that glyphosate has low hazard potential to mammals, however, the International Agency for Research on Cancer (IARC) concluded in March 2015 that it is probably carcinogenic. The IARC conclusion was not confirmed by the EU assessment or the recent joint WHO/FAO evaluation, both using additional evidence. Glyphosate is not the first topic of disagreement between IARC and regulatory evaluations, but has received greater attention. This review presents the scientific basis of the glyphosate health assessment conducted within the European Union (EU) renewal process, and explains the differences in the carcinogenicity assessment with IARC. Use of different data sets, particularly on long-term toxicity/carcinogenicity in rodents, could partially explain the divergent views; but methodological differences in the evaluation of the available evidence have been identified. The EU assessment did not identify a carcinogenicity hazard, revised the toxicological profile proposing new toxicological reference values, and conducted a risk assessment for some representatives uses. Two complementary exposure assessments, human-biomonitoring and food-residues-monitoring, suggests that actual exposure levels are below these reference values and do not represent a public concern.

Response to the reply by C. J. Portier and P. Clausing, concerning our review “Glyphosate toxicity and carcinogenicity: a review of the scientific basis of the European Union assessment and its differences with IARC”

commenting rounds and the public consultation (EFSA 2015b). Although our response will be restricted to the EFSA assessment presented in Tarazona et al. (2017), it is worth noting the similarities in term of complementarity and transparency between the EFSA process under the pesticides regulation and the ECHA process under Regulation (EC) No 1272/2008. Germany as RMS under the Regulation (EC) No 1107/2009 (Germany 2015) and Dossier Submitter under the Regulation (EC) No 1272/2008 (BAuA 2016) expresses the views of the German experts, while EFSA (2015a, b) reports the view of the experts involved in the EFSA peer-review. The RAC Opinion (ECHA 2017) represents the view of the ECHA Committee for Risk Assessment. Portier and Clausing (2017) are suggesting apparent contradictions between the different views regarding the evaluation of study N. But in our opinion, this participates to the strength of the EU complementarity value. Different approaches for the weight of evidence are presented in a transparent way, allowing the scrutiny by the scientific community and interested groups. Even more important, despite different views on how to approach specific issues such as the reliability and relevance of study N, the weights of evidence converge and there is full consensus on the final conclusion, thus confirming that including or excluding study N does not change the overall assessment. EFSA decided to exclude study N due to concerns on the health status of the animal population, identified by US EPA (USEPA 2016), and confirmed by EFSA experts. Viral infections were not investigated by the study authors; therefore, EFSA’s confirmation focused on the health status and was based on indirect indications in the study report, supported by complementary evidence. The GLP status of the study (mandatory for industry-sponsored studies) implies that the test system should be free of any disease or condition that might interfere with the purpose or conduct of We welcome the opportunity for having an evidence-based scientific discussion on glyphosate’s carcinogenicity. We note that all of the findings in Table 1 of the Reply by Portier and Clausing (2017) have been available in the public domain in the supplemental data tables published by Greim et al. (2015; available online since February 2015). In addition, some of these findings were also raised in the report by IARC, but were not considered further. Although not explicitly mentioned by Portier and Clausing, it is relevant to indicate that, following a request to access to documents by four Members of the European Parliament, both authors got access to the findings and raw data of the unpublished industry sponsored studies on the carcinogenicity and genotoxicity of glyphosate submitted to EFSA; and even more important, that this information will be provided, under request, to any other person interested in scrutinizing the EFSA assessment and weight of evidence presented in our review. Two basic values of the EU assessments on pesticides are complementarity and transparency. The first is based on the peer-review principle, with an initial assessment by experts of the rapporteur member state (RMS), which is peer-reviewed by EFSA in close collaboration with experts from other Member States, and resulting in the EFSA Conclusion (EFSA 2015a). Transparency is ensured by publishing all assessments in a peer review report, which includes the comments and responses received during the different