Men with a high probability of exposure to formaldehyde, such as funeral directors, have an almost 3-fold greater rate of death related to amyotrophic lateral sclerosis (ALS) than those with no exposure to the chemical, new research shows.
"The study is important because, unfortunately, we know almost nothing about what causes ALS, which is 100% fatal within a very short time period," study author Andrea Roberts, research associate, Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, told Medscape Medical News.
Although some genes have been implicated in ALS, they are responsible for a very small number of cases, and no environmental factors have clearly been shown to cause the disease, said Dr Roberts. "So any evidence that we can get just to direct us as to what might possibly be a cause is helpful."
The study is published online July 13 in the Journal of Neurology Neurosurgery & Psychiatry.
The investigators used data from the National Longitudinal Mortality Study (NLMS), a probability sample of the US civilian noninstitutionalized population, with occupational data collected prospectively. They used a formaldehyde exposure matrix and calculated the intensity (frequency and level of exposure) and probability (likelihood of any exposure) for each occupation and industry. They coded these exposures as none, low, medium, or high.
NLMS records were matched to the National Death Index. ALS deaths were defined according to the International Classification of Diseases, 9th and 10th Revisions, as those with ALS as the underlying or contributing cause of death.
The study sample included 794,541 men and 674,694 women aged 25 years and older when surveyed.
Researchers calculated hazard ratios (HRs) separately for each probability and intensity level, using those with no exposure to formaldehyde as the reference group. They did this for both men and women.
They also calculated HRs for each intensity level using the same reference group and restricting exposed respondents to those with a high probability of exposure.
In the sample, 99 women and 493 men had jobs with high-probability and high-intensity formaldehyde exposure. All the men and all but 1 of the women were funeral directors.
After adjustment for race/ethnicity, education, and household income, the HR for ALS mortality among those with a high probability of formaldehyde exposure vs no exposure was 2.98 (95% confidence interval [CI], 0.78 - 11.30).
The study did not find a link between formaldehyde exposure and ALS in women. The sample of exposed women, said the authors, may have been too small to detect a possible connection to ALS.
According to Dr Roberts, female funeral directors in the United States are more likely than their male counterparts to interact with bereaved clients and less likely to perform embalming, where exposure to formaldehyde occurs.
"It's possible that even though they're in the same profession as men, their exposure to formaldehyde and other hazards is much lower," she said.
The researchers also conducted 5 sensitivity analyses. One of these excluded the first 5 years of follow-up, while others separately included respondents up to age 75 years only, those older than age 35 years, those older than age 50 years, and those who were employed at enrollment.
"We wanted to sharpen up our diagnosis of ALS to make sure it was accurate" since the condition is more likely to be misdiagnosed as people get older and experience multiple medical problems, explained Dr Roberts.
Another aim of the subanalyses was to ensure that the job-related formaldehyde measure was accurate, explained Dr Roberts.
"In this national mortality study, respondents could have been aged 30 doing one job with a certain level of exposure and then 10 years later they might be in a different job with a different level of exposure, and we can't capture that. So we tried to restrict it to people who were older when they enrolled in this study."
All the subset analyses found an elevated HR for high probability of formaldehyde exposure compared with no exposure. The strongest association (HR, 4.76; 95% CI, 1.16 - 19.49) was for respondents aged 50 to 75 years at enrollment.
This, said Dr Roberts, makes sense because it's during much of that period of life when "you're pretty stable in your job."
According to studies cited by the authors, funeral directors are exposed to 0.15 to 9.2 ppm (particulates per million) of formaldehyde during an embalming. The chemical is absorbed through the skin during this procedure at 49.2 mg/h.
This occurs even though funeral directors likely wear protective gloves, gowns, and masks and use some sort of ventilation, said Dr Roberts.
In addition to formaldehyde exposure varying depending on the number of embalming procedures funeral directors perform, how careful they are, and the physical structure of their environment, it also depends on the condition of the cadaver they're working on, said Dr Roberts.
"With bodies that are completely intact, formaldehyde exposure is lower, but with people who have been in an accident or had surgery and are open a bit, more chemicals are used in the embalming," she added.
Dr Roberts noted that under such circumstances, funeral directors could be exposed to other biopathogens. "These are people who have died and if they died of an infectious disease or some bacterial infection, then the embalmer is potentially exposed to those."
While other jobs — for example, those in the textile industry and in biology laboratories — may involve exposure to formaldehyde, not everyone in those fields is exposed to the same degree. "For lab workers, it might be that some of them are highly exposed and some have no exposure at all," said Dr Roberts.
But funeral directors are much more likely to be exposed across the board.
Experiments with animal models show that formaldehyde can cause significant neurologic damage. According to Dr Roberts, it makes tau protein misfold, which causes neurons to die, increases the membrane permeability of cell mitochondria, and causes oxidative damage.
A logical next study would be one that looks only at funeral directors to see whether the current findings stand up and to perhaps uncover a missing link tying formaldehyde exposure to ALS, said Dr Roberts.
Commenting on the study for Medscape Medial News, Ryan Seals, postdoctoral research fellow, Harvard T.H. Chan School of Public Health, Boston, who was not involved in the research, noted that this is the first prospective, nationally representative study to attempt to estimate the amount or intensity of individual formaldehyde exposure.
However, he noted that the study does have some limitations.
"In particular, the analysis relied on one self-reported occupational measurement. And despite the size of the initial surveys, the study was hampered by small numbers of exposed cases. All of the statistically significant conclusions rely on only two ALS deaths out of the hundreds of thousands who responded, which should give us pause."
Because of the few women, it's impossible to tell whether the lack of highly exposed women in the study was due to random chance or because the nature of their work in the field is different from that of men, said Dr Seals.
However, he noted that some evidence suggests that smoking, a suspected cause of ALS, is a stronger cause among women than men.
"It seems that the authors were not able to adjust for smoking in the main analyses, so it's conceivable that differences in smoking rates between men and women could influence the results."
The authors provide "quite a good summary" of the plausible ways in which formaldehyde could cause ALS, said Dr Seals. "I would only add that there is also some evidence that formaldehyde can increase permeability in the blood-brain barrier, potentially increasing the brain's exposure to other neurotoxins."
Formaldehyde, he added, has acute neurologic effects, including headache, memory loss, sleep disturbances, and irritability. It also causes skin and respiratory irritation and is a suspected cause of nasopharyngeal cancer, he said.
Dr Seals stressed that anyone handling formaldehyde should take precautions but noted that not all protective equipment eliminates risks. "Some types of gloves, for example, are more permeable to formaldehyde, and can begin to break down within an hour or two."
As anyone who has used formaldehyde in a high school or college chemistry class knows, the chemical has a distinctive smell, said Dr Seals. "Inhalation is a common exposure route, and unless appropriate masks are worn, considerable exposure could be accrued by simply breathing it in."
This study alone is not sufficient to change guidelines pertaining to formaldehyde exposure, said Dr Seals. "Future studies will be needed to assess whether the current recommended average exposure maximum of 0.75 ppm should be reconsidered in light of a possible relationship with ALS."
Dr Roberts and Dr Seals have disclosed no relevant financial relationships.
J Neurol Neurosurg Psychiatry. Published online July 13, 2015.
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Cite this: Formaldehyde Exposure Linked to ALS - Medscape - Jul 13, 2015.