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Neurodevelopmental toxicity: still more questions than answers We read with interest Grandjean and Landrigan’s Review of developmental neurotoxins, 1 in which glyphosate herbicide was listed as a human neurotoxicant on the basis of a case report by Malhotra and colleagues.2 The individual in this case report was a 71-year-old man who was unresponsive and in cardiogenic shock with a profound metabolic acidaemia (pH 7·13) and lactic acidosis (7·1 mmol/L; normal levels are 0·5–1·6 mmol/L). He received ventilator support and venovenous haemodiafiltration and was presumptively managed as having organophosphate i ntoxication, receiving 239 mg of atropine and 4 g of pralidoxime over an unspecified period of time. He had a persistent, unexplained osmolar gap, suggesting the presence of an unrecognised toxicant. He spent 10 days in intensive care (details of sedation, if any, were not provided) and was discharged after full recovery on day 16. Malhotra and colleagues stated that this case raises “a suspicion of direct cerebral toxicity”, but drew no conclusion that glyphosate is a recognised neurotoxicant and noted that inquiry into other components of the ingested product was indicated. Although intentional glyphosatesurfactant ingestions can cause cardiovascular compromise,3 we are not aware of neurological compromise being seen without significant multiorgan dysfunction and metabolic disturbance. Permanent neurological sequelae after large ingestions have not been reported in the absence of profound circulatory and metabolic compromise and glyphosate has not shown neurotoxicity in animal studies.4,5 The encephalopathic and neurobehavioral changes in this case are quite adequately explained by www.thelancet.com/neurology Vol 13 July 2014

the multiple insults to the patient, including anoxic or hypoxic injury, metabolic disturbances, haemodiafiltration, massive anti cholinergic (atropine) doses, a possible unexplained osmotically active toxin, and the environment of the intensive care unit in which the patient was treated.6 Grandjean and Landrigan’s conclusion that glyphosate is a recognised human neurotoxicant is unjustified on the basis of this case report, and there is no consensus of toxicity in the scientific literature. This fact, in turn, raises serious questions about the overall rigor of their Review, which seems to ignore fundamentals of dose response, limitations of epidemiological investigation, and actualities of chemical use and exposure.7,8 Should the authors look for further evidence of glyphosate neurotoxicity, we would point out that the two case reports of parkinsonism following glyphosate exposure similarly offer no evidence of causation: one reports parkinsonism at age 44 following 3 years of exposure to multiple materials in a pesticide formulation facility 9 and the other reports parkinsonism with an onset of 30 days after a single incidental dermal exposure to glyphosate-surfactant herbicide. 10 After 40 years of manufacturing and global use for weed control, the lack of epidemiological evidence linking glyphosate to neurotoxicity, including Parkinson’s disease, is telling.11,12 DAG and DAS are full time employees of Monsanto, a manufacturer of glyphosate-based herbicide products.

*Daniel A Goldstein, David A Saltmiras [email protected] Monsanto, St Louis, MO 63017, USA (DAG, DAS) 1

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Grandjean P, Landrigan PJ. Neurobehavioral effects of developmental toxicity. Lancet Neurol 2014; 13: 330–38. Malhotra RC, Ghia DK, Cordato DJ, Beran RG. Glyphosate-surfactant herbicide-induced reversible encephalopathy. J Clin Neurosci 2010; 17: 1472–73.

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Bradberry SM, Proudfoot AT, Vale JA. Glyphosate poisoning. Toxicol Rev 2004; 23: 159–67. European Commission. Review report for the active substance glyphosate. Glyphosate 6511/VI/99-final 21 January 2002. http://ec. europa.eu/food/plant/protection/evaluation/ existactive/list1_glyphosate_en.pdf (accessed March 3, 2014). WHO/FAO. Pesticides residues in food—2004. Report of the Joint FAO/WHO Meeting on Pesticide Residues. Part II Toxicological Evaluations. http://whqlibdoc.who.int/ publications/2006/9241665203_eng.pdf (accessed March 3, 2014). Meagher DJ. Delirium: optimizing management. BMJ 2010; 322: 144–49. http://www.bmj.com/cgi/content/ full/322/7279/144 (accessed March 3, 2014). Science Media Center. Expert reaction to industrial chemicals and neurodevelopmental disorders. http://www.sciencemediacentre. org/22728/ (accessed Feb 25, 2014). Burns CJ, McIntosh LJ, Mink PJ, Jurek AM, Li AA. Pesticide exposure and neurodevelopmental outcomes: review of the epidemiologic and animal studies. J Toxicol Environ Health Part B: Critical Reviews 2013; 16: 127–283. Wang G, Fan XN, Tan YY, Chen Q, Chen SD. Parkinsonism after chronic occupational exposure to glyphosate. Parkinsonism Relat Disord 2011; 17: 486–87. Barbosa EG, Leite CC. Parkinsonism after glycine-derivate exposure. Mov Disord, 2001; 16: 565–68 Kamel F, Tanner CM, Umbach DM, et al. Pesticide exposure and self-reported Parkinson’s disease in the Agricultural Health Study. Am J Epidemiol 2007; 165: 364–74. Mink PJ, Mandel JS, Lundin JI, Sceurman BK. Epidemiologic studies of glyphosate and non-cancer health outcomes: a review. Regul Toxicol Pharmacol 2011; 61: 172–84.

In their Review of neurological toxicants,1 Grandjean and Landrigan make unsubstantiated claims and misquote previous studies to pull together heterogeneous elements and drugs into a group of substances termed neurotoxicants. The investigators’ claim of new data is undermined by 24 of the cited references being their own previous, mostly review articles and their new list of toxicants includes permethrin on the basis of findings from one study that, in fact, showed that permethrin did not affect development.2 Their “strong evidence” for adding fluoride was a finding from Grandjean’s own review of older Chinese studies. Contrary to their statement—“Confounding from other substances seemed unlikely in most of these studies”—findings 645

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from many previous meta-analyses have shown the faults of using intelligence quotient (IQ) data from countries with highly polluted air and water; non-validated IQ tests; poor controls for parent IQ, socioeconomics, and other variables; and studying mega-doses in animals and in human beings.3,4 By contrast with this review of Chinese studies, all of problematic methodological robustness, more than 3000 studies of the safety of water fluoridation stretch over 65 years. During this time, as fluoridation increased from 0% to 72% of US households, average US IQs have not decreased, but have instead increased by 15 points.5 The investigators also added manganese to their list of neurotoxicants writing that “might cause” or has been “linked to” neurological disorders: prenatal exposure to ADHD and postnatal exposure to parkinsonism. However, recent reviews have shown no link between manganese and ADHD or parkinsonism.6,7 Their assumption that “neurotoxicants might lurk undiscovered” behind even low doses of all chemicals can’t be disproved. But it denies dose-response concepts. By seeing manganese and fluoride alongside repeated analogies to lead, a reader would naturally associate these elements with the situation with lead, in which no safe level of exposure exists. Manganese, however, as a trace element, does have a safe level. Paediatricians appreciate careful neurodevelopment research. But many question the reality of such an expanding ‘pandemic’. Besides rising IQs, findings from large surveillance studies from the National Health Interview Survey and Metropolitan Atlanta Developmental Disabilities Surveillance Program showed stableto-falling rates of mental retardation and cerebral palsy between the 1990s and 2005.8 Even researchers who see a possible increase in neurodevelopmental disorders 646

attribute it to increases in screening, preterm births, survival of children with genetic or congenital defects, multiple births (from assisted reproduction), and school funding for children with medical diagnoses.9 Table 3 ignores all such factors except prematurity, instead they reference their own studies and those of a frequent co-author, David Bellinger. Bellinger proposed10 an interesting, but unproven model of IQ points lost from environmental versus other causes. He admitted, however, that for factors such as fluoride and arsenic, available meta-analyses are not suitable for calculating IQ points lost. The investigators’ conclusion asks scientists to reanalyse the strength of evidence needed to constitute proof for designating substances as neurotoxicants. Their limitless precautionary principle is inferior to the present continual analysis of data by the US Environmental Agency, the US Centers for Disease Control and Prevention, and other existing health organisations. I declare no competing interests.

Virginia Feldman [email protected] Kaiser Permanente Northwest, Portland, OR 97219, USA 1

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Grandjean P, Landrigan PJ. Neurobehavioral effects of developmental toxicity. Lancet Neurol 2014; 13: 330–38. Horton MK, Rundle A, Camann DE, Barr DB, Rauh VA, Whyatt RM. Impact of prenatal exposure to piperonyl butoxide and permethrin on 36-month development. Pediatrics 2011; 127: e699–706. Bazian Ltd. Independent critical appraisal of studies reporting an association between fluoride in drinking water and IQ. London, UK: Bazian Ltd, 2009. Scientific Committee on Health & Environmental Risk of the European Union. Opinion on critical review of any new evidence on the hazard profile, health effects, and human exposure to fluoride and the fluoridating agents of drinking water—16 May, 2011. http://ec.europa.eu/health/scientific_ committees/environmental_risks/docs/ scher_o_139.pdf (accessed March 7, 2014). Neisser U. Risings scores on intelligence tests. American Scientist 1997; 85: 440–47. Kieburtz K, Wunderle KP. Parkinson’s disease: evidence for environmental risk factors. Mov Disord 2013; 28: 8–13.

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Jankovic J. Etiology and pathogenesis of Parkinson disease. http://www.uptodate.com/ contents/etiology-and-pathogenesis-ofparkinson-disease?source=search_result&searc h=Etiology+and+pathogenesis+of+Parkinson+ disease&selectedTitle=1~150 (accessed April 20, 2014). CDC. CDC data on NHIS (National Health Interview Survey) and MADDSP (Metropolitan Atlanta Developmental Disabilities Surveillance Program): Yeargin-Allsopp M. www.ucsf.com.2008/MOC08001/ YearginAllsopDDAcrossTheLifespan (accessed March 6, 2014) Boyle CA, Boulet S, Schieve LA, et al. Trends in the Prevalence of Developmental Disabilities in US Children, 1997–2008 Pediatrics 2011; 127: 1034–42. Bellinger D. A strategy for comparing the contributions of environmental chemicals and other risk factors to neurodevelopment in children. Environ Health Perspect 2012; 120: 501–07.

In their Review, Grandjean and Landrigan expressed concern about the neurodevelopmental toxicity of methylmercury, 1 but did not assess the dangers of serious and widespread inhalation exposures to elemental mercury vapour (Hg⁰) from its magico-religious uses in some Caribbean and Latino communities and the presumptive associated latent epidemic of developmental neurotoxicity this constitutes. In the belief that it attracts good and repels evil, practitioners of folk magic and Caribbean religions including Espiritismo, Santería, and Voodoo, sprinkle mercury on floors and furnishings where it accumulates levels of mercury vapour, about 80% of which is inhaled or absorbed. The Hg+ ion is the toxic moiety in methylmercury. Mercury vapour, like methylmercury, is lipophilic and readily crosses the placental and blood–brain barriers and enters breast milk. The mean weight of mercury sold by botanicas for ritualistic use is about 10 g. Mercury spilt during ritualistic ceremonies that permeates flooring and furnishings can persist for decades, during which time it continually produces mercury vapour. Hence, most exposures are probably second-hand, from ritualistic spills by previous occupants of an individual’s dwelling. 2,3 Unlike methylmercury www.thelancet.com/neurology Vol 13 July 2014

Neurodevelopmental toxicity: still more questions than answers.

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