Common Solvents Strongly Tied to MS Risk

Pauline Anderson

July 05, 2018

There is a strong association between exposure to organic solvents and multiple sclerosis (MS) risk, especially among those who smoke and carry a genetic risk, new research shows.

Individuals with a family history of MS can't do anything about their genetic risk for the disease, lead study author Anna Karin Hedström, MD, PhD, Department of Clinical Neuroscience and Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden, told Medscape Medical News.

"But what they can do is avoid smoking and also try to avoid at least unnecessary exposure to organic solvents."

The combination of these factors increases the disease risk, especially in those carrying a certain allele within the human leukocyte antigen (HLA) complex.

The study was published online July 3 in Neurology.

Common Chemicals

Organic solvents are hydrocarbon compounds widely used in many industries, including paint and varnishing, dry cleaning, adhesives, and cosmetics.

Research indicates that the cause of MS involves specific genetic factors. The authors note that the strongest genetic associations with MS are located within the HLA complex.

The HLA-DRB1*15 allele increases the risk for MS, with an odds ratio (OR) of about 3, whereas the HLA-A*02 allele of the HLA-A locus exerts a protective effect, with an OR of about 0.5.

Environmental factors also influence MS risk. These include Epstein-Barr virus infection, vitamin D status, sun exposure, adolescent obesity, and smoking.

Research suggests that smoke exposure has a considerably higher association with MS among those with a genetic susceptibility to the disease, said the authors.

Exposure to organic solvents seems to be a risk factor for developing a variety of autoimmune diseases, including MS. A meta-analysis based on 15 studies found that the OR for MS among participants exposed to organic solvents was 1.53 (95% confidence interval [CI], 1.03 - 2.29).

Exposure, Smoking, Genetics Data

The new study included 2042 patients with newly diagnosed MS from the Epidemiological Investigation of Multiple Sclerosis, a Swedish population-based case-control study that includes the general population aged 16 to 70 years. The mean age at MS onset was 34 years, and the median duration from disease onset to diagnosis was 1.0 year.

From the national population register, researchers randomly selected two controls per case, matched for age, sex, and residential area.

Investigators collected Information on environmental exposures and lifestyle factors using a standardized questionnaire. Among other things, participants were asked to provide detailed information on occupational exposures to organic solvents, painting products, and varnish.

Those who were exposed, a group that included painters, printers, chemical engineers, and farmers, were asked to be specific and detailed about the duration of their exposure.

Study participants also provided detailed information about smoking history.

Blood samples were available from 88% of cases and 59% of controls who completed the questionnaire. Participants who donated blood were genotyped for the HLA-A and HLA-DRB1 alleles.

Researchers classified participants according to carriage of any HLA-DRB1*15 allele vs no carriage, and according to carriage of any HLA-A*02 allele vs no carriage.

Lung Irritants

Adjusted analyses showed a significant association between exposure to organic solvents and increased risk for MS (OR, 1.5; 95% CI, 1.2 - 1.8; P = .0004). Statistically significant trends showed increasing MS risk with increasing duration of exposure.

It wasn't possible to isolate individual solvents that may be more harmful when it comes to MS risk. Hedström noted that participants often don't know exactly what they were exposed to, and solvents are often mixed together, making it difficult to accurately quantify exposure.

The analysis uncovered various interactions among MS risk genes, smoking, and organic solvents. For example, for those exposed to both smoking and organic solvents but who did not have the relevant genes, the adjusted OR was 5.0 (95% CI, 3.0 - 8.4; P < .0001).

Both smoking and organic solvents are irritants, and researchers believe they may lead to inflammation in the lungs, said Hedström.

"That could contribute to an immune response that eventually results in MS, especially among those who have a genetic susceptibility to the disease," she said.

Risk Reduction

Indeed, in participants who were exposed to organic solvents and had genetic risk, the adjusted OR was 6.7 (95% CI, 3.7 - 12.1; P < .0001); for those who were exposed to smoking and had genetic risk, the adjusted OR was 7.9 (95% CI, 6.0 - 10.4; P < .0001).

In addition, those exposed to both smoking and organic solvents and who carry HLA-DRB1*15 and lack HLA-A*02 had a 30-fold increased risk for MS compared with nonexposed participants without the genetic risk factors (adjusted OR, 30.3; 95% CI, 11.7 - 78.3; P < .0001).

"We know that smoking interacts with high-risk genes independently of organic solvents, and there's an interaction between organic solvents and the same risk genes regardless if you're a smoker or not, but then if you have both these risk factors, and have high genetic susceptibility, then the risk is very much increased," said Hedström.

The researchers only had access to incident cases of newly diagnosed MS, using the McDonald criteria, and so were unable to determine whether the risks differed with the various types of MS, which include relapsing-remitting, primary progressive, and secondary progressive.

It's important to identify lifestyle and environmental factors related to MS because these are preventable, noted Hedström.

The new study not only underlines the importance of avoiding these preventable exposures but provides information "that will help us better understand the mechanism behind the disease," said Hedström.

Recall Bias

Commenting on the study for Medscape Medical News, Barbara Giesser, MD, professor of clinical neurology, David Geffen School of Medicine, and clinical director of the MS Program, University of California at Los Angeles, said that while it's "well controlled" and "intriguing," it's based on participant recall.

"So it's not clear how much actual exposure to solvents the cases really had."

Geisser noted that the authors suggest that pulmonary inflammation from organic solvents, in the appropriate genetic setting, may act in a similar fashion as smoking in raising risks for MS.

"This study adds to the body of literature that suggest that developing MS is a combination of both genetic and environmental factors, but more data are needed."

In addition, authors of an accompanying editorial, Jack S. Bell, BM, BCh, University of Oxford Medical School, and Gabriele C. DeLuca, MD, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, United Kingdom, said the study was well-powered and that the population-based case-control approach was "appropriate for addressing the proposed hypothesis."

Toxic Cocktail?

Just how exposure to organic solvents leads to MS is unclear, although several lines of evidence point to an influence on the adaptive immune system, they write.

One such line of evidence, they said, comes from multiple animal and in vitro studies showing direct effects of organic solvents on immune cell function, such as changes in DNA methylation in lymphocytes, altered T-cell populations, and aberrant cytokine secretion.

Another line of evidence is that the principal access points for organic solvent exposure — the olfactory system, lung, gut, and skin — "are highly immunologically active and therefore poised to facilitate gene-environment interactions relevant to MS," the editorialists add.

Organic solvents also have direct effects on the central nervous system (CNS), which may be relevant to gene-environment interactions that contribute to MS risk, they added.

Future work identifying specific causal organic solvents, along with their precise influence on immunologic function, blood-brain barrier, and CNS integrity in MS, is "urgently needed," write Bell and DeLuca.

"How the cocktail of HLA, organic solvents, and smoking contributes so significantly to MS risk also warrants investigation."

The study was supported by grants from the Swedish Medical Research Council, Swedish Research Council for Health, Working Life and Welfare, Knut and Alice Wallenberg Foundation, AFA insurance, the Swedish Brain Foundation, and Neuro Sweden. Hedström, Giesser, and Bell have disclosed no relevant financial relationships. DeLuca has served on the scientific advisory board of Bayer Schering; has received travel funding/speaker honoraria from Bayer Schering, Novartis, Genzyme, and Merck Serono; serves on the editorial board of the Multiple Sclerosis Journal; and has received research support from Merck Serono, Biomedical Research Centre (NIHR, Oxford), and the Medical Research Council (United Kingdom).

Neurology. Published online July 3, 2018. Abstract, Editorial

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