Correspondence
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
2
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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6
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8
9
10
11
12
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
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
2
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.
3 4
5
6
7
8
9
10
11
12
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
