Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease, believed to affect as many as 30,000 Americans. A hundred and fifty years after its discovery, the disease remains mysterious and devastating, striking without warning.

Teasing out the constellation of factors that underlie this complex disorder has been a challenge for researchers. In addition to a hereditary component for some ALS and related neurodegenerative diseases such as Alzheimer's disease, researchers have pointed to a broad range environmental agents as possible risk factors.

In a new meta-analysis of available ALS literature, Professor Rolf Halden and two doctoral students at Arizona State University Biodesign Institute explore environmental influences potentially linked to the disease, using rigorous quantitative methods. The study also examines the distribution of ALS over space and time, correlating geographic data with exposure risks and lifestyle or occupational hazards.

The new findings will help researchers begin to fill in the many remaining blank spaces in the full portrait of this disease, which the study projects will affect around 22,650 Americans by 2040.

Doctoral student and lead author of the study, Melanie Newell, points out that "narrowing possible risk factors to a likely subset will hasten the work needed to determine whether these factors are merely associated or actually causal to ALS. The realities for patients and caregivers of this horrific disease could be significantly improved by reducing the delay of diagnosis and avoidable (occupational) exposures early in life."

Halden, director of the Biodesign Center for Environmental Health Engineering, adds that "the role of environmental factors in diseases, not just neurodegenerative diseases such as ALS, continues to be understudied and underappreciated. Many disease trends in industrialized nations are increasing to an extent and within a rather short time scale which simply cannot be explained by inherently slow genetic changes. To improve U.S. and global health outcomes, studying environment factors is key."

The review recently appeared in the journal Science of the Total Environment.

The brain under assault

ALS, also known as Lou Gehrig's disease, named for the famous baseball player who suffered from the illness, causes degeneration of motor nerve cells in the brain (upper motor neurons) and spinal cord (lower motor neurons), resulting in increasingly severe paralysis. Other symptoms include twitching and cramping of muscles, loss of motor control in the hands and arms, weakness and fatigue, shortness of breath and difficulty breathing and swallowing.

The disease is somewhat more common in men than in women, for reasons researchers are still trying to puzzle out. ALS usually strikes between the ages of 55 and 75. The disease is incurable, with most ALS patients undergoing rapid deterioration, dying 3-5 years initial diagnosis.

Around 5-10% of all cases are the result of so-called familial ALS, which occurs when two or more family members are stricken with the disease. Such patients tend to deteriorate more rapidly than ALS patients who are not related, typically succumbing to the ailment 1-2 years after diagnosis. Although gene mutations have been associated with the disease, these represent only 1-2% of all ALS cases. The overwhelming majority of ALS cases lack any clearly defined root cause. Diet, injury and exposure to a broad range of potentially harmful chemicals have all been implicated. These latter are the focus of the current overview.

A new read on ALS

The large-scale analysis of available literature on ALS encompassed some 1,710 papers, identifying 258 that met the stringent criteria for inclusion in the study. Two methodologies were used in the data analysis to reduce the probability of errors. A total of 83 environmental chemicals were assessed during the review. When combined, the two methods pointed to a group of seven chemicals, exposure to which correlates with increased risk of developing ALS.

Chemicals topping the list of environmental hazards in need of further research are β-N-methylamino-L-alanine (BMAA), formaldehyde, selenium, and four heavy metals: manganese, mercury, zinc, and copper (in order of decreasing significance). The new study also describes some of the challenges facing researchers in their efforts to home in on the range of culprits for this enigmatic disorder.

The study notes that ALS cases are not evenly distributed around the globe. Some geographic hot spots have been identified from historical data, particularly in the Western Pacific region.

Such data offer tantalizing suggestions that environmental factors specific to certain areas may be contributing to the ALS burden. Examples include the Chamorros people of the Mariana Islands, including Guam. The area reached a peak in 1956 of 100 ALS cases per 100,000 persons. Later, New Guinea reached the highest prevalence ever reported in 1963, with 147 cases per 100,000 persons. In the case of New Guinea, rates remain well above the global average today. Screening has ruled out genetic factors for most of these cases, strongly implicating environmental correlates.

Hidden threats

Toxic chemicals accumulating in the environment are good candidates for causative agents of ALS and other neurodegenerative diseases, as they emerge in associative studies and further are known, in some cases, to trigger genetic and epigenetic changes in the body. However, the picture becomes hazy as the effects of exposure to recognized neurotoxins such as metals, solvents, pharmacological agents, or mixtures of these are colored by endogenous factors specific to each individual, including genetic predisposition and gene expression.

Use of a disease origin investigative tool, termed the Bradford Hill criteria, allowed the ASU researchers to tease apart confounding factors to more accurately measure, weigh and interpret disease risks by examining the interaction of multiple causal criteria. For a given chemical compound or group of chemicals to be deemed causative, (not merely associated) with ALS, the Bradford Hill approach requires 9 specific conditions to be met. To further validate the results, a literature search of geographic exposure events associated with ALS cases was also applied.

Of the top seven chemicals showing strong association with ALS, only BMAA met all the Bradford Hill criteria, though other chemicals remain strongly implicated and require further research to determine their role. Because exposure to toxic chemicals can lead to a heightened risk for ALS, particular occupations making liberal use of such chemicals are cited, including construction, paperwork, agriculture, electrical work, medical professions, military service and manufacturing.

In the case of BMAA, listed in the study as the greatest chemical threat, exposures are likely the result of dietary intake by consuming seafood from waters contaminated with cyanobacteria or from eating the cycad plant, which contains both BMAA and cycasin, another neurotoxin. In addition to farming and fishing, a variety of other occupations showed a positive association between known chemical exposure and ALS incidence, including mining, manufacture of electrical equipment, hobbies using heavy metals, welding (due to manganese exposure) and dentistry (due to mercury exposure).

Assembling the puzzle of ALS

The prevalence of ALS is on the upswing in the U.S. Although the National Amyotrophic Lateral Sclerosis Registry shows 5,000 people are diagnosed each year with ALS, the current study's modelling predicts in excess of 6,400 potential annual diagnoses. ALS cases are predicted to increase to 22,654 in 2040, and to 209,830 in 2240, in the United States. Globally, increases in ALS caseloads are expected to be greatest in China, the U.S. and India.

Given the complex interplay of factors, including exposure to multiple chemicals, occupational risk, lifestyle choices, age, sex, and genetic predisposition, developing a clear-cut pattern of causality will remain a challenge, particularly in the absence of early diagnostic signposts or biomarkers of ALS. Nevertheless, hypothesis-driven studies of known risk factors and their effects on disease incidence may be designed based on the results of this literature analysis. The research therefore offers hope and a productive path forward in battling this perplexing and devastating disorder.