results should be interpreted with caution, given the reliance of both studies on self-re- ported exposure as well as the small number of exposed cases in each study. In evaluating associations between work- place exposures and diseases, it is important to consider other environmental factors such as smoking that might modify the neuro- toxicity of the exposures. Although meth- odologic problems should be considered as a possible explanation for our findings, we found no consistent differences in covari- ates between smokers and nonsmokers, and there is no apparent reason why nonsmok- ing cases would be more likely than smoking cases to report workplace exposures. Beyond methodologic issues, biological explanations should also be considered. It is possible, for example, that chemical exposures from smok- ing are so great that the additional exposure to workplace chemicals becomes irrelevant. Another possible explanation is induction by smoking of metabolic enzymes. n-Hexane is hydroxylated at the 2 and 5 positions pri- marily by cytochrome P450 (CYP) 2E1, leading to formation of the neurotoxic metab- olite 2,5-hexanedione (Zhang et al. 2006). Although smoking induces CYP2E1, sug- gesting that smokers should be more sensi- tive to neurotoxic effects of hexane, smokers may also have increased levels of other P450 isozymes (e.g., CYP1A1 and CYP1A2), lead- ing to increased detoxification of n-hexane. In addition, constituents of cigarette smoke may compete with n-hexane for CYP2E1, forcing the latter into detoxifying pathways. Our study has several strengths. First, ALS diagnoses were confirmed by board- certified neurologists using well-recognized diagnostic criteria. Second, we had detailed information on workplace exposures in addi- tion to job and industry titles, independent inference of specific chemical exposures by an industrial hygienist, and information on important covariates such as smoking status. The limitations of the present study should also be appreciated. First, it is a case–control study with self-reported exposure. However, the presence of some associations (e.g., lead– ALS) but not others (e.g., mercury–ALS) mitigates to some extent concern about recall bias. Second, ALS cases were enrolled from tertiary care centers and might not be rep- resentative of cases in the population; for example, they might tend to live longer (Lee et al. 1995), so an association with an expo- sure that shortened survival might be missed. However, 85% of cases were enrolled within 1 year and the remainder within 2 years of diagnosis; survival bias should thus have min- imal impact. Further, the median survival time between first diagnosis and death was No. of controls (n = 253) Overall No. of cases (n =109) No. of controls (n = 148) Smokers No. of cases (n = 77) Table 5. Chemical exposures determined by an industrial hygienist and the risk of ALS , overall and stratified by smoking.a VM&P, varnish makers and painters. aIndividuals with missing information on a specific chemical were excluded from the analysis of that chemical; individuals never exposed to the chemical in the question served as the reference group for that chemical. bCalculated from logistic regression models; all models were adjusted for age (< 56, 56–65, and > 65 years), sex, area of residence (Boston metro- politan area, eastern Massachusetts, and rest of New England), smoking, and educational level. cCalculated from logistic regression models; all models were adjusted for age (< 56, 56–65, and > 65 years), sex, area of residence (Boston metropolitan area, eastern Massachusetts, and rest of New England), and educational level. Environmental Health Perspectives • volume 117 | number 9 | September 2009 Workplace exposures and ALS 28 months (Kamel et al. 2008), comparable to survival time in other studies (Logroscino et al. 2008). Third, we did not find a mono- tonic increase of ORs with increasing duration of most exposures. This phenomenon is fre- quently seen in occupational studies and has several potential explanations (Stayner et al. Table 6. Workplace formaldehyde exposure and the risk of ALS.a No. of No. of controls cases OR (n = 253) (n = 109) (95% CI)b Never 204 89 Ref. Ever 49 20 0.8 (0.5–1.5) Exposure probabilityc 0–1 7 2 0.6 (0.1–2.8) 1 27 9 0.7 (0.3–1.6) 2 15 9 1.3 (0.5–3.2) p-Value for trend 0.50 Weighted exposure durationd ≤ 10,000 hr 14 7 1.1 (0.4–2.8) 10,001–40,000 hr 19 8 0.8 (0.3–1.9) > 40,000 hr 16 5 0.7 (0.2–2.0) p-Value for trend 0.45 aIndividuals who never had a formaldehyde-related occu- pation served as the reference group. bCalculated from logistic regression models; all models were adjusted for age (< 56, 56–65, and > 65 years), sex, area of residence (Boston metropolitan area, eastern Massachusetts, and rest of New England), smoking, and educational level. cHighest probability of exposure ever experienced: three- level scale in 0–1, 1, and 2. dLevel 0–1 was given a weight of 0.5; level 1 was given a weight of 1; and level 2 was given a weight of 2. Nonsmokers No. of cases (n = 32) 12 14 22 19 11 8 9 16 11 7 14 8 11 8 8 11 11 7 13 9 10 7 19 9 8 15 OR (95% CI)c 2.5 (1.0–6.3) 4.1 (1.6–8.9) 2.7 (1.1–6.8) 2.5 (1.0–6.2) 2.0 (0.8–5.2) 2.5 (0.9–7.2) 1.5 (0.6–4.0) 2.7 (1.1–6.6) 2.6 (1.0–6.8) 6.3 (1.6–24.1) 5.1 (1.9–13.7) 2.4 (0.9–6.9) 3.4 (1.3–9.6) 1.9 (0.7–5.2) 1.5 (0.5–4.2) 2.6 (1.0–6.8) 1.8 (0.7–4.6) 1.5 (0.5–4.3) 1.4 (0.6–3.5) 1.5 (0.6–4.0) 1.7 (0.7–4.3) 1.5 (0.5–4.3) 2.4 (1.0–5.9) 1.5 (0.6–4.6) 1.5 (0.5–4.2) 3.1 (1.2–8.1) 1391 Exposure Acetone Aliphatic chlorinated hydrocarbons Aliphatic hydrocarbons Aromatic hydrocarbons Benzene Benzidine Carbon tetrachloride Cyclohexane Ethyl acetate Ethylene/propylene glycol Glycol ethers Heptane n-Hexane Methanol Methyl chloroform Methyl ethyl ketone Methylene chloride Methyl tert-butyl ether Naphtha (VM&P) Perchloroethylene Stoddard solvent Tetraethyl lead Toluene Trichloroethylene Trichlorotrifluoroethane Xylene 60 67 134 111 74 37 72 87 57 23 53 36 44 47 59 57 69 56 92 72 68 56 114 72 59 77 33 42 65 52 39 21 33 46 32 17 33 23 29 24 28 32 33 29 46 35 35 29 55 35 28 37 OR (95% CI)b 1.3 (0.8–2.3) 1.6 (0.9–2.7) 1.2 (0.7–1.9) 1.1 (0.7–1.8) 1.2 (0.7–2.0) 1.4 (0.8–2.7) 0.9 (0.6–1.6) 1.2 (0.8–2.1) 1.3 (0.8–2.3) 1.6 (0.8–3.3) 1.6 (0.9–2.7) 1.5 (0.8–2.7) 1.7 (1.0–3.0) 1.1 (0.6–2.0) 1.0 (0.6–1.7) 1.3 (0.8–2.3) 1.0 (0.6–1.7) 1.1 (0.6–1.9) 1.1 (0.7–1.8) 1.0 (0.6–1.7) 1.1 (0.7–1.9) 1.1 (0.6–1.9) 1.1 (0.7–1.8) 1.0 (0.6–1.7) 1.0 (0.6–1.7) 1.2 (0.7–1.9) 38 46 85 69 49 22 49 57 37 17 35 22 28 30 40 37 45 37 58 49 44 37 71 49 40 49 21 28 43 33 28 13 24 30 21 10 19 15 18 16 20 21 22 22 33 26 25 22 36 26 20 22 OR (95% CI)c 0.9 (0.4–1.8) 1.0 (0.5–2.0) 0.7 (0.4–1.3) 0.7 (0.4–1.3) 0.9 (0.5–1.8) 1.1 (0.5–2.4) 0.8 (0.4–1.5) 0.8 (0.4–1.6) 1.0 (0.5–1.9) 0.9 (0.3–2.4) 0.9 (0.4–1.8) 1.2 (0.5–2.6) 1.2 (0.6–2.4) 0.8 (0.4–1.7) 0.8 (0.4–1.5) 1.0 (0.5–1.9) 0.7 (0.4–1.4) 1.0 (0.5–1.9) 0.9 (0.5–1.8) 0.8 (0.4–1.6) 0.9 (0.4–1.7) 1.0 (0.5–1.9) 0.8 (0.4–1.4) 0.8 (0.4–1.6) 0.8 (0.4–1.5) 0.7 (0.4–1.4) No. of controls (n = 105) 22 21 49 42 25 15 23 30 20 6 18 14 16 17 19 20 24 19 34 23 23 19 43 23 19 28