Metals and ALS under the microscope

Exposure to metals has been associated for some time with chronic neurological disorders such as amyotrophic lateral sclerosis (ALS). But much is still unknown about a possible relationship and it is also not easy to investigate. If you start from patients and then look back, there is a risk that the exposure information collected will be distorted. Therefore, prospectively collected information has recently been used by conducting research in the database of the EPIC study.

EPIC study

De European Prospective Investigation into Cancer and Nutrition (EPIC) studies have been set up to investigate the role of biological and lifestyle factors, genetic background and the interplay of genetic and non-genetic factors on chronic diseases including cancer ( At the European level, the cohort has more than 500.000 participants who have now been followed for about 15 years. Participants come from Denmark, France, Germany, Greece, Italy, Netherlands, Norway, Spain, Sweden and Great Britain

In the Netherlands we participate through EPIC-NL; this is a merger of the Prospect-EPIC cohort (coordinated by the Julius Center) and the Morgen-EPIC cohort (coordinated by RIVM, Bilthoven). It is a cohort of more than 40.000 men and women from Amsterdam, Doetinchem, Maastricht and Utrecht and the surrounding area, who were between 1993 and 1997 years old at the time of recruitment in the period 20-70.

Amyotrophic Lateral Sclerosis ALS

ALS is a serious progressive and fatal neurodegenerative disorder of the central and peripheral nervous system of as yet unknown etiology. In the disease, motor nerve cells are lost leading to progressive nerve weakness, difficulty swallowing and death from respiratory failure. Most patients die 3 to 4 years after the onset of symptoms, although this time varies widely. ALS is the most common neurodegenerative motor neuron disease in adults with an estimated incidence of 2,6–3 per 100.000 person-years.

One of the risk factors would be exposure to metals as can occur in a variety of occupations. Think, for example, of welding, installation work, making metal products, smelters, etc. However, the general population is also exposed to metals when they occur in food, drinking water, air pollution, smoking, certain medications and dietary supplements.

Periodic Table – Photo via Pixabay

Research group

The study looked at the concentrations of various metals measured in the blood that was collected when people were included in the EPIC cohort. The study group included the 117 people (65% women, 16% smokers) who died from ALS, according to the death certificate. The control group of 319 people (13% smokers) are comparable to the research group in age, gender and research center. The blood was checked for arsenic, cadmium, copper, lead, manganese, mercury, selenium and zinc. The concentrations found have been compared with ALS mortality. The median time between blood draw and death from ALS was 8 years, ranging from 1 to 15 years.

Interesting results for three metals

Ultimately, the study only yielded deviating values ​​for cadmium, lead and zinc. The concentrations of metals found are divided into three groups and the highest of these tertiles is compared with the lowest. For example, an Odds Ratio (OR) has been determined. This produces the following ORs:

  • cadmium –OR = 2,04 with 95% confidence interval (CI) 1,08 – 3,87
  • Lead –OR = 1,89 with 95% CI 0,97 – 3,67
  • Zinc –OR = 0,50 with 95% CI 0,27 – 0,97


This study shows that exposure to lead and cadmium may be associated with an increase in risk of ALS, while exposure to zinc appears to protect. The results for lead are in line with the results of previous research in exposed occupational groups. The fact that this is a relatively low additional risk may be appropriate for a disease with multifactorial causes where lead exposure is one of many causative factors. Genetic susceptibility can also play an important role here.

The results for cadmium and zinc are new and have not been studied much further. For cadmium, cigarette smoking should also be considered. This is one of the few risk factors for which an association with ALS has been better established, although the mechanism is still unclear. However, smoking cigarettes also absorbs metals into the body and smokers generally have a higher concentration of cadmium in the body than non-smokers. The same applies to lead, while the zinc and selenium concentrations in smokers are lower. This is also visible in this study, but the relationship between lead and cadmium and ALS persists when corrected for smoking.


Peters, S., Broberg, K., Gallo, V., Levi, M., Kippler, M., Vineis, P., ... & Vermeulen, R. (2021). Blood metal levels and amyotrophic lateral sclerosis risk: a prospective cohort. Annals of Neurology89(1), 125-133.