Abstract. A retrospective case-control study of occupational heavy metal exposure was conducted using 66 amyotropliic lateral sclerosis (ALS) patients and 66 age- and sex- matched controls. Cases were ascertained primarily through a neurology support and research clinic. The self-administered questionnaire probed potential exposure to nine heavy metals: aluminum, lead, lead alkyl, magnesium, manganese, mercury, mercury alkyl, nickel and selenium. Using McNemar's test and a Mantel Haenszel extended analysis, no association was found between heavy metal exposure and the pathogenesis of ALS in this patient population. Demographic factors, fracture history, immunizations, travel and other variables were similar in ALS patients and controls.
Amyotrophic lateral sclerosis (ALS) is considered a major enigma in neurology. Its symptomatology is associated with the selective damage of the upper and lower motor neurons, leading to death within an average of 2-5 years. ALS appears to be distributed rather uniformly around the world, with mortality rates averaging 1.5 per 100,000 population, incidence imaging mortality at 1-2 per 100,000, and prevalence at 5-7 per 100,000. In the course of searching for etiological factors, the role of heavy metals, lead and mercury in particular, has surfaced for discussion. Other factors of proposed etiologic significance include aging [1], viral infection [2, 3], disease of nerve growth factor [4], deficiency of DNA repair enzymes [5], impaired immune function [6], and fractures and skeletal abnormalities [7,8].
Concern that ALS may be related to a history of increased heavy metal exposure is not unexpected, given that lead and mercury are endemic envi ronmental neurotoxins. Wilson in 1907 and Brown in 1954 respectively reported chronic lead poisoning and chronic mercurialism in farmers as causing ALS-like symptomology [9]. There is evidence to support [8,10- 12] and refute [7, 13-15] a hypothesis of heavy metal exposure as a risk factor in ALS. Roelofs-Iverson et al. [16] recently reported a case-control study conducted at the Mayo Clinic where occupational exposure to heavy metals was significantly higher among cases than controls. The metals were not studied individually and no information was obtained on the duration of exposure. The present study is unique and complementary in that it probes exposures to specific metals and the duration of exposure.
This study was carried out from January 1985 to May 1985. Sampling was done from a case listing developed by the Center for Neurologic Study, a patient support and research facility in San Diego, California. In addition, letters were sent to 60 area neurologists detailing the goals of the study, and seeking to increase case identification.
Identification of Cases
(1) Objective diagnostic criteria: clinical picture consisting of (a) progressive muscular
atrophy and weakness, (b) variable signs of fasiculation, (c) pyramidal tract involvement,
and (d) no sensory involvement. (2) Eligibility criteria: incident cases diagnosed during
1975-1985.
Definition of Controls
Friends or neighbors of ALS patients, not a former co-worker, matched 1 to 1 case on
age (+ 5 years) and sex, and free of known neurologic disease.
Data Collection
Data collection was by means of a mailed self-administered questionnaire. Sixty ALS
cases and 15 surrogates for ALS patients responded; 66 were used after screening for
completeness and data quality. There were 33 men, mean age at diagnosis 55.2; and 33
women, mean age at diagnosis 57.7 (fig. 1). There were no twins. Each ALS case was given
an additional questionnaire to be completed by a neighbor/friend of similar age. Subjects
completing the questionnaire responded to demographic items on race, sex, marital status,
and military status. Occupational history of jobs with potential exposure to individual
heavy metals (Al, Pb, Pb alkyl, Hg, Hg alkyl, Mg, Mn, Ni, Se), as delimited by the National
Institute for Occupational Health and Safety (NIOSH), was examined [17-20]. This
included 293 distinct occupations where exposure to specific heavy metals was at least a
possibility according to NIOSH. Other environmental and medical items included were
travel history (Mariana Islands and southern and western Pacific), history of polio, thyroid
disorders, fractures, and immunization history, with specific reference to swine flu vacci
nation.
Analysis
Retaining matching, McNemar's formula was used to test the hypothesis that the
odds ratio is unity for potential heavy metal exposure, number of fractures, metabolic
deficiencies and history of immunization. Ninety-five percent approximate confidence
intervals (Cls) were constructed [21]. For heavy metal analysis, only jobs performed by a
subject for more than 6 months were included. The Mantel Haenszel (MH) extended
(dose-response) analysis [22], ignoring matching, was calculated to test for a significant
progressive increase or decrease in the odds ratio with increased duration of occupational
exposure.
Demographics
There were no significant differences between the groups on demographic variables of ethnicity
(X2 = 1.33, p = 0.51), history of military service
(X2 = 1.02, p = 0.60), marital status (X2 = 2.59, p = 0.63), or education
(X2 = 4.62, p = 0.20). Table I summarizes the demographic profile of patients and controls.
Antecedent Events
Occupational Heavy Metal Exposure. The types of occupations re
ported demonstrated that the assumption of constant occupational expo
sure ratios between males and females was not met. Among women, only 2
cases reported potential occupational heavy metal exposure (table II).
Therefore, in calculation of the matched odds ratio for heavy metal exposures, only males were used. No association was found between cases and controls on the variable of heavy metal occupational exposure. The
matched analysis is presented in table III. Since there were so few exposures
to the other metals, only lead, mercury and 'all metals' were analyzed. Ninety-five percent Cls are given.
To examine any possible dose-response phenomenon, an age-adjusted
MH extended analysis was performed, with matching suspended, on
months of lead and mercury exposures. It should be noted that some cells
contained zero and did not contribute to the denominator in the odds ratios
calculated from the MH dose-response test. Zero months exposure was
compared to 1-60 months (level 1), Psi MHPB = 8.397,
Psi MHHG = undefined; and zero months exposure compared
to 61+ months exposure (level II), Psi MHPB = 0.974,
Psi MHHG = 1.106. No increased risk was shown with increased
occupational exposure to lead or mercury.
Swine Flu Vaccination and Other Immunizations. There was no signif icant difference between cases and controls on history of immunizations, including the 1976 swine flue vaccine. Forty-five percent of ALS males and 48% control males had received at least one immunization, as did 50% ALS females and 45% control females.
Thyroid/Mineral Disorders. The number of reported mineral and thyroid disorders was similar in ALS patients and control subjects.
Travel History. Eighteen percent of ALS males had traveled to both the Mariana Islands and Japan; 30% to Japan and 21% to the Marianas. Control subjects reported travel to both places at a significantly lower rate of 9%, yet reported similar rates to individual countries (30% Japan, 18% Marianas). In female respondents, 9% of both groups had traveled to Japan, and 6% of both groups visited the Marianas. Military travel by the male subjects seems to account for the difference between male and female percentages.
Poliomyelitis. No significant difference was found between cases and controls on history of paralytic poliomyelitis.
Fractures. Comparing the number of individuals with at least one frac ture, no significant difference was found between ALS and control subjects.