Critical Confluence: Gene Variants, Insecticide Exposure May Increase Childhood Brain Tumor Risk

Modern diseases often seem to occur in isolation, but many are now known to emerge from a complex web or pattern of conditions linked together by certain underlying biological mechanisms and processes. With the help of large disease databases, medical scientists have begun to discern how such patterns occur over the course of a lifetime. A new review focused on developmental immunotoxicology explores how this integrative perspective might inspire novel strategies for lowering the risk and prevalence of immune-based diseases influenced by environmental stimuli [EHP 118(8):1091–1099; Dietert et al.]. 
 
Many chronic diseases share three common features: 1) early-life exposures to chemical agents or pathogens, 2) evidence of immune insult or dysfunction, and 3) the appearance of disease biomarkers in exposed children although disease itself may not manifest until later in life. One example of interlinked disease conditions highlighted by the authors is metabolic syndrome, defined as the co-occurrence of at least three of five conditions: insulin resistance, obesity, high blood pressure, elevated triglycerides, and reduced HDL cholesterol. 
 
Immune dysfunction is central to the underlying physiology of metabolic syndrome, and the authors posit that the seeds of such dysfunction may be planted in childhood. They describe pre- and postnatal exposures to environmental risk factors that produce postnatal lipid dysregulation and immune dysfunction. However, it is not yet known whether immune dysfunction is an underlying cause of metabolic syndrome or simply an associated or disease-facilitating characteristic. 
 
The practical key to preventing metabolic syndrome may lie in treatments that address overall patterns and their progression, not just the initial presenting condition. “For those patterns of disease with immune involvement,” the authors write, “preventing the underlying immune dysfunction is the single most effective option to minimize the risk of one or more chronic diseases later in life.” This will require more information about risk factors for immune dysfunction that are encountered during development or childhood. Therefore, the authors also recommend that chemicals and pharmaceuticals be tested for developmental immunotoxicity end points; currently, safety assessments are based solely on adult exposures. 
 
The authors say patterns of disease can be used to better predict, prevent, and treat diseases associated with an immune-related pattern of diseases, and may also serve as the basis for environmental protection and testing to prevent exposure to developmental immunotoxicants that may contribute to multiple interconnected diseases. But pattern-based evaluation, prevention, and treatment will require a shift from the prevailing single-organ approach to disease classification and management.

The National Institute for Occupational Safety and Health, which conducts research on workplace safety, has no recommended exposure limit guidelines for nanomaterials, and the Occupational Safety and Health Administration has no permissible exposure limit specific to engineered nanomaterials. However, recent animal toxicology studies suggest nanomaterials may cause specific adverse health effects. For example, carbon nanotubes have been shown to induce inflammation and oxidative stress in animal models.
To assess the magnitude of potential exposure in a laboratory setting, a team of researchers measured the amount of carbonaceous nanomaterials (CNMs) released into the air during routine material handling and processing tasks in standard environmental matrices such as artificial river water. The authors evaluated nano material releases using real-time particle counters and transmission electron microscopy.
The research team found that CNMs became airborne when they were handled and weighed in the lab. Smaller structures, with an aerodynamic diameter of less than 1 µm, scattered more readily than larger particles.
A surprise finding was the substantial release of CNMs during sonication, a common laboratory process used to break apart agglomerates of nanomaterials into aqueous dispersions. Sonication produced a CNM-containing mist that could be inhaled by workers or that could leave CNMs on laboratory surfaces after the water evaporated. The extent of release during sonication was increased when natural organic matter was added to the solution, as is often done to simulate conditions in the environment. Hydrophobic CNMs exhibited higher airborne particle number concentrations during handling than during sonication, whereas hydrophilic CNMs exhibited the opposite trend.
These findings contradict the belief that risks of exposure are minimized when working with nanomaterials in liquid suspensions. The authors believe this field case study is the first to demonstrate the release of CNMs during sonication and also the first to detail nanomaterial release in an environmental laboratory. They caution that more robust statistically based experimental research is needed to evaluate CNM exposure among laboratory workers. Until then, they urge researchers working with nanomaterials to use appropriate personal protective equipment in the laboratory and to adopt adequate engineering controls to minimize their exposure. During the flu season each year, combating the different strains of the influenza virus becomes a public health priority, with treatment dependent upon two groups of antiviral drugs: neuraminidase inhibitors and M2 ion channel inhibitors. Oseltamivir phosphate, marketed as Tamiflu, is a popular neuraminidase inhibitor widely used to treat flu symptoms. Oseltamivir carboxylate (OC), Tamiflu's active metabolite, is known to withstand activated sludge treatment at sewage treatment plants (STPs), but less is known about how much OC may make its way into waterways that receive STP effluent. Now a new study conducted in Kyoto City, Japan, According to the World Health Organization, between 250,000 and 500,000 people die each year from influenza, and each year, millions of people take Tamiflu to battle flu symptoms. After the sewage treatment process, the excreted active metabolite remains in STP effluent and travels to waterways where effluent is discharged.
The investigators in the current study collected samples from STP effluent and from river water on three different occasions: at the beginning of the flu season, during the peak period, and 2 weeks after the peak period. Using solid-phase extraction followed by liquid chromatography-tandem mass spectrometry, they measured the highest concentration of OC, 293.3 ng/L, in an STP discharge sample collected during the peak of the flu season. Concentration amounts were higher in effluent from STPs that used traditional activated sludge treatment; in contrast, effluent from plants that used advanced ozonation as tertiary treatment contained significantly lower OC levels (37.9 ng/L). River water samples showed a range of OC levels from 6.6 to 190 ng/L during the peak of the flu season.
Previous research indicates OC concentrations ranging from 80 to 230 ng/L will disable 50% of the influenza virus. This level of exposure is most likely to kill virus particles that are particularly susceptible to OC, while selecting for viruses that are resistant to the drug's effects. The authors note, "During a common flu season, waterfowl can ingest large quantities of OC with virus. . . .

Exposing waterfowl infected with influenza A virus to elevated levels of OC in open waterways could trigger the development of Tamiflu-resistant viral strains."
The authors suggest ozonation as tertiary treatment that may reduce OC load in STP effluent. They also recommend conducting further investigations to determine the fate of antiviral drugs at every interval of the STP process.
Tanya Tillett, MA, of Durham, North Carolina, is a staff writer/editor for EHP. She has been on the EHP staff since 2000 and has represented the journal at national and international conferences.

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Resistance in the making? Potential influenza A host meets potential source of active Tamiflu metabolite

Gene Variants, Insecticide Exposure May Increase Childhood Brain Tumor Risk
Epidemiologic data have suggested a link between pesticide exposures and childhood brain tumors. The link may be specific to insecticides such as organophosphorus and carbamate compounds, which are known to target the nervous system. Previously published work  investigated the role of individual genetic variation with a focus on paraoxonase (PON1), a key enzyme in the metabolism of organophosphorus insecticides commonly used in homes at the time but now banned for residential use. This work showed that children with brain tumors were more likely to carry a common single-nucelotide polymorphism (SNP) gene variant in the promoter region of the PON1 gene (PON1 C-108T ) than other children, and that the association between this SNP and brain tumors was stronger in children with a history of home insecticide exposure. Research in an expanded study population now provides additional evidence that exposure to insecticides, paired with specific metabolism gene variants, may increase the risk of childhood brain tumors [EHP 118:144-149; Searles Nielsen et al.].
The research population included 201 children in California and Washington who had been diagnosed with a primary tumor of the brain, cranial nerves, or meninges between 1984 and 1991, as well as 285 children from the same geographic areas who served as controls. All children were aged 10 years or younger. Genetic information was extracted from archived dried blood spots used for routine screening tests when the children were born. In addition to PON1 C-108T , the genetic analysis covered 7 other gene polymorphisms that might influence the children's ability to metabolize insecticides. Interviews with the children's mothers provided data on prenatal and childhood exposures to insecticides in the home.
Between the cases and controls, there was little difference in the prevalence of any of the polymorphisms. For cases, more of the mothers reported in-home insecticide use during pregnancy, but in-home treatment during childhood was more common among controls. Data analysis confirmed the original observation that children exposed to insecticides were more likely to have brain tumors if they also carried the PON1 C-108T SNP. Evidence of similar interactions also were observed with two other gene variants, FMO1 C-9536A and BCHE A539T , which also may affect the ability to detoxify organophosphorus and/or carbamate insecticides.
These findings suggest that children who are exposed to insecticides at a young age may have a greater risk of developing brain tumors if they carry these and possibly other polymorphisms. Larger studies are needed to confirm the findings, and environmental and biological measurements of specific pesticides, inclusion of more polymorphisms, and detailed information on exposure timing and dose would strengthen support for causal effects of insecticides and gene-environment interactions on the risk of childhood brain tumors.
Julia R. Barrett, MS, ELS, a Madison, Wisconsin-based science writer and editor, has written for EHP since 1996. She is a member of the National Association of Science Writers and the Board of Editors in the Life Sciences.