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Pesticide in Milk May Have Caused PD-Like Damage

ARTICLE IN BRIEF

Using data from postmortem biopsies culled as part of the Honolulu-Asia Aging Study, investigators reported that men who drank the most milk had the greatest residue levels of heptachlor epoxide and averaged 40 percent less neuronal density in the substantia nigra, suggesting a possible association between the pesticide residue found in milk and risk of developing Parkinson's disease.

Brains of deceased Hawaiian men who drank more than two cups of milk each day before the late 1980s, when there was widespread use of the pesticide heptachlor in pineapple fields, showed residue of the agent and significant loss of neurons in the subtantia nigra characteristic of Parkinson's disease, researchers reported in a paper in the December 9 online edition of Neurology.

The investigators used data from postmortem biopsies culled as part of the Honolulu-Asia Aging Study, a longitudinal investigation of rates, risk factors, and brain abnormalities associated with cognitive decline and dementia in older Japanese-American men. They focused on heptachlor epoxide exposure. When animals and bacteria are exposed to heptachlor, they break it down into heptachlor epoxide.

Prior to 1988, heptachlor epoxide was widely used in Hawaiian pineapple fields. The pesticide can persist for long periods of time, and byproducts of harvested pineapple plants were commonly added to cattle feed when it was still used. The pesticide can also contaminate well water.

STUDY METHODOLOGY, RESULTS

Autopsies of 447 male participants were reviewed with postmortem evaluation of neuronal density, together with information on milk intake. Of 116 non-smoking men, heptachlor epoxide residue was found in the brains of 90 percent of those who drank the most milk (at least 16 ounces of milk every day), compared with 63.4 percent for those who drank no milk (p<0.001). And those who drank at least two glasses of milk per day averaged 40 percent less neuronal density in the substantia nigra, a part of the brain involved in motor planning, learning, and eye movement. Deficits in the area are recognized as a signature of PD.

The same was not true among smokers and ex-smokers, however, suggesting that smoking may convey some unknown neuroprotective effect, as has been reported in other research of some neurodegenerative diseases.

The men, who were between the ages of 45 and 68, had medical and dietary information collected between 1965 and 1968 and postmortem brain examinations performed from 1992 to 2004. Most of the men in the study had been tracked for more than 30 years or until death.

Because the dietary information in the database was limited, however, it was unclear if milk was the sole cause of the residue or neuronal loss, the researchers noted.

“It takes a 50 percent loss of these cells before the classic symptoms of PD appear, giving us a lot of time for intervention,” said lead author Robert D. Abbott, PhD, a professor of epidemiology at the Center for Epidemiologic Research in Asia at the Shiga University of Medical Science in Otsu, Japan.

“The idea is that if we can stop cell death before it is too late, we could, in theory, prevent some PD, but the problem is that neurodegeneration can predate the classic motor symptoms of PD by decades,” he told Neurology Today.

STUDY LIMITATIONS

It was very difficult for the researchers to accurately assess actual milk intake because the analysis was based on records of self-reported dietary data over decades. Moreover, there was no available data to show that any of the milk contained heptachlor epoxide, so it is possible that the results were due to chance, Dr. Abbott said.

The investigators also found that neuron density in the ventrolateral, ventromedial, and dorsolateral quadrants of the sustantia nigra continued to decline with increasing milk intake even after heptachlor epoxide was banned.

Dr. Abbott said the group's work will continue and will include exposure to other pesticides. “Whether milk contamination with organochlorine pesticides has a role in neurodegeneration warrants further study,” he said, “and surveys from recent deaths are currently ongoing so the sample size will increase. It is a top priority for us to analyze these samples when they become available.”

EXPERTS COMMENT

In an editorial accompanying the study, Honglei Chen, MD, PhD, a principal investigator with the National Institute of Environmental Health Sciences, and Karen Marder, MD, chief of the division of aging and dementia in the department of neurology at Columbia University, wrote that the findings should be interpreted within the context of the study's limitations.

While the investigation suggests heptachlor epoxide contamination was a plausible reason for neuronal loss, they wrote, “another potential explanation may be that milk consumption lowers plasma urate, which in turn leads to higher risk of PD over time. However, serum uric acid was not related to substantia nigra neuronal density in the study.”

Lorene Nelson, PhD, an associate professor of health research and policy at Stanford University School of Medicine, who was not involved with the study, said the risk of exposure to heptachlor epoxide for the average person today is extremely low.

She told Neurology Today that it is difficult to speculate about whether the findings have broader implications for Hawaii residents who were alive when the pesticide was still being used, but there is little reason for concern for most mainland US residents.

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DR. ROBERT D. ABBOTT: “Whether milk contamination with organochlorine pesticides has a role in neurodegeneration warrants further study, and surveys from recent deaths are currently ongoing so the sample size will increase. It is a top priority for us to analyze these samples when they become available.”

“If the findings are causal, then it is plausible that other residents of Hawaii from that time period who consumed large quantities of contaminated milk could be at increased risk of PD later in life, but this is speculative,” she said.

She added that she could not find any reports of heptachlor-contaminated milk supplies in the US aside from the Hawaiian supply before the ban.

“I believe that this is the first study that has sought to determine whether the association of milk consumption with PD could be due to the presence of a contaminant like heptachlor. It is unlikely that any other investigative group would have the study population and resources to carry out such an analysis,” she said.

In 2010, researchers in France reported that men with certain gene variants who were exposed to certain pesticides had 3.5 times the risk of developing PD. The investigators suggested that these individuals' brains could not flush out toxic chemicals as efficiently as those of people with other gene variants. This would implicate environmental and genetic factors in the risk of developing the disease.

One of those investigators, Alexis Elbaz, MD, PhD, research director at the French National Institute of Health and National Research (INSERM) Center for Research in Epidemiology and Population Health, told Neurology Today that at least five prospective cohort studies, three in the US and two in Europe, have shown a link between milk intake and the risk of PD, and there is toxicological evidence that heptachlor is toxic for dopaminergic neurons in mice.

“This is the first study to bring evidence that the relation between milk consumption and PD may be mediated by milk contamination by heptachlor,” he noted. “It shows the great potential and important contributions of large-scale long-term cohort studies and of the implementation of brain donation and autopsies as part of these studies.”

He cautioned that the number of persons who drank the most milk in the study was small — only 12 drank more than 16 ounces per day. “Hence, some caution is needed in the interpretation of these findings,” he said.

It is also unclear if the findings can explain the association between milk consumption and PD in other cohorts, because it is not known if milk was also contaminated with heptachlor or another organochlorine in studies conducted in other parts of the world.

While there are strict regulations in Western countries, some of these compounds are still used in developing countries. “Therefore, these findings may be more relevant nowadays in these countries,” Dr. Elbaz said.

He noted that organochlorine pesticides like heptachlor are highly lipophilic and are known to accumulate in the brain, where they can be measured years after the exposure. This is not true for other toxicants, so it is possible that milk was contaminated with other toxicants that could not be measured at autopsy, Dr. Elbaz said.

“Additional toxicological studies are needed to better characterize its toxicity and the mechanisms that underlie it,” he said.

LINK UP FOR MORE INFORMATION:

•. Abbott RD, Ross GW, Petrovitch KH, et al. Mid-life Milk Consumption and substantia nigra neuron density at death http://www.neurology.org/content/early/2015/12/09/WNL.0000000000002254.short?sid=8666d590-bef9-41e5-8c0b-315338d49052. Neurology 2015; Epub 2015 Dec. 9.
    •. Chen H, Marder K. Milk consumption and the risk of nigral degeneration http://www.neurology.org/content/early/2015/12/09/WNL.0000000000002268.short?sid=0b12b389-06a5-4ffb-8778-d8ae82e10681. Neurology 2015;Epub Dec. 9.
      •. Chen H, O'Reilly EO, McCullough ML, et al. Consumption of dairy products and risk of Parkinson's disease http://aje.oxfordjournals.org/content/165/9/998.abstract?sid=eb8109f7-cf30-4f49-85cf-4154b67199b6. Am J Epidemiol 2007;165:998–1006.
        •. Fleming L, Mann JB, Bean J, et al. Parkinson's disease and brain levels of organochlorine pesticides http://onlinelibrary.wiley.com/doi/10.1002/ana.410360119/abstract. Ann Neurol 1994;36:100–103.
          •. Chen H, Zhang SM, Hernan MA, et al. Diet and Parkinson's disease: a potential role of dairy products in men http://onlinelibrary.wiley.com/doi/10.1002/ana.10381/abstract. Ann Neurol 2002;52:793–801.
            •. Dutheil F, Beaune P, Elbaz A, et al. Interaction between ABCB1 and professional exposure to organochlorine insecticides in Parkinson disease http://archneur.jamanetwork.com/article.aspx?articleid=800503. Arch Neurol 2010;67:739–745.
              •. CDC Fact sheet on heptachlor exposure: http://bit.ly/CDC-heptachlor