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  1. Re: Amyotrophic lateral sclerosis and occupational exposure to 2,4-D

    We appreciate the interest taken in our study by Dr. Freedman.[1] At the heart of the discussion are the interpretation of statistical significance in our study,[2] and the lack of statistical significance in others. A critical point in valuing causation is the weight of the evidence to be placed upon the nonsignificant increase of nonspecific exposures observed in human studies of amyotrophic lateral sclerosis (ALS) compared to the weight placed upon controlled animal studies specific to the herbicide, 2,4-dichlorophenoxyacetic acid (2,4-D).

    I agree with Dr. Freedman that undue reliance upon statistical significance is ill advised. He is correct that the case-control studies cited in our paper showed elevated odds ratios,[3][4][5][6] but there is no evidence that any subjects were actually exposed to 2,4-D since the exposures were limited to "pesticides" and "agricultural chemicals" and "herbicides". The cohort studies examined workers who were definitely exposed to 2,4-D and thus provide a more valid assessment of risk even though they are less powerful than the case-control studies.[7][8] The cohort studies of 2,4-D do not consistently show increased risk of ALS.

    The associations observed in the case-control studies are clearly unsupported by the experimental studies that have been conducted on 2,4-D. Environmental causes of ALS remain unknown. If future epidemiological studies investigate the neurotoxicity of herbicides such as 2,4-D, the researchers must improve upon the status quo of surrogate exposure information used in case-control studies or perform further studies of the 2,4-D workers. Epidemiologist must make a commitment to quality exposure assessment of individual pesticides, perhaps coupled with biomonitoring, to address the putative health concerns associated with pesticides.

    CJ Burns

    1 Freeman DM. Mortality in chemical workers potentially exposed to 2,4-dichlorophenoxyacetic acid (2,4-D) 1945 – 94: an update. Occup Environ Med 2001.
    2 Burns CJ, Beard KKI, Cartmill JB. Mortality in chemical workers potentially exposed to 2,4-dichlorophenoxyacetic acid 1945-94: an update. Occup Environ Med 2001;58:24-30.
    3 Chancellor AM, Slattery JM, Fraser H, et al. Risk factors for motor neuron disease: a case-control study based on patients from the Scottish Motor Neuron Disease Register. J Neurol Neurosurg Psychiatry 1993;56:1200- 6.
    4 Deapen DM, Henderson BE. A case-control study of amyotrophic lateral sclerosis. Am J Epidemiol 1986;123:790-9.
    5 Saviettieri G, Salemi G, Arcara A, et al. A case-control study of amyotrophic lateral sclerosis. Neuroepidemiology 1991;10:242-5.
    6 McGuire V, Longstreth WT Jr, Nelson LM, et al. Occupational exposures and amyotrophic lateral sclerosis. Am J Epidemiol 1997;145:1076-88.
    7 Zahm SH. Mortality study of pesticide applicators and other employees of a lawn care service company. J Occup Environ Med 1997;39:1055-67.
    8 Coggon D, Pannett B, Winter P. Mortality and incidence of cancer at four factories making phenoxy herbicides. Br J Ind Med 1991;48:173-8.

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  2. Amyotrophic lateral sclerosis and occupational exposure to 2,4-dichlorophenoxyacetic

    Editor

    Burns et al.[1] report a significant excess of deaths due to amyotrophic lateral sclerosis (ALS) in a cohort of Dow employees potentially exposed to the herbicide 2,4-Dichlorophenoxyacetic (2,4-D), but then argue against the plausibility of a causal association, concluding that the association "is not consistent with previous human or animal studies".

    This conclusion and the authors' characterisation of the relevant epidemiologic studies appear to rely entirely upon statistical significance, which downplays the importance of their finding. Firstly, the authors state that "cohort studies of people with exposure to 2,4-D (have not) reported increased rates of ALS," citing two studies,[2] [3] both of which have limited power to detect the risk of ALS. One of the two studies assessed risk in a cohort that was quite young with a relatively short follow up,[2] and would therefore be unlikely to detect an increased risk for a disease such as ALS, which has a much older median age at onset. Burns et al then go on to state that "exposure to pesticides and agricultural chemicals have shown no significant association in several studies"(emphasis added).[1]

    In each of the three case-control studies cited, however, ALS was positively associated with pesticides or agricultural chemicals, with reported ORs of 1.4,[4] 2.0,[5] and 3.0,[6] although the associations do not reach statistical significance. Finally, Burns et al refer to a case-control study,[7] which found a significant association between ALS and pesticides, but, they emphasise, "did not find a significant association of exposure to herbicides".[1] The association between ALS and herbicide exposure was increased, however, and the lack of statistical significance reflected, at least in part, small numbers.

    None of this is meant to say that the finding of a significant association between ALS and 2,4-D is conclusive. The finding is, however, consistent with several previous studies and, instead of being played down, warrants serious attention in future studies.

    D M Freedman
    National Cancer Institute
    Division of Cancer Epidemiology and Genetics
    USA

    1. Burns CJ, Beard KK, Cartmill JB. Mortality in chemical workers potentially exposed to 2,4-dichlorophenoxyacetic acid (2,4-D) 1945-94: an update. Occup Environ Med 2001;58:24-30.
    2. Zahm SH. Mortality study of pesticide applicators and other employees of a lawn care service company. J Occup Environ Med 1997;39:1055-67.
    3. Coggon D, Pannett B, Winter P. Mortality and incidence of cancer at four factories making phenoxy herbicides. Br J Ind Med 1991;48:173-8.
    4. Chancellor AM, Slattery JM, Fraser H, et al. Risk factors for motor neuron disease: a case-control study based on patients from the Scottish Motor Neuron Disease Register. J Neurol Neurosurg Psychiatry 1993;56:1200-6.
    5. Deapen DM, Henderson BE. A case-control study of amyotrophic lateral sclerosis. Am J Epidemiol 1986;123:790-9.
    6. Saviettieri G, Salemi G, Arcara A, et al. A case-control study of amyotrophic lateral sclerosis. Neuroepidemiology 1991;10:242-5.
    7.McGuire V, Longstreth WT Jr, Nelson LM, et al. Occupational exposures and amyotrophic lateral sclerosis. Am J Epidem 1997;145:1076-88.

    Submit response
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