Ind Med Research Articles

Enhancing Credibility of Chemical Safety Studies: No Consensus

I commend Conrad and Becker (2011) for frankly discussing the criteria by which to judge data quality in chemical risk assessment. Those criteria revolve tightly around financial conflict of interests. I agree with Conrad and Becker (2011) that industry seems likely to continue to perform the toxicity tests in risk assessment. That is due to what I call the “GLP [Good Laboratory Practices] shield.” Industry’s compliance with GLP has caused many tens of thousands of published independent chronic toxicity studies—any of which might have determined the allowable “safe” daily dose of a chemical—to be excluded from premarket approval risk assessments and substituted with financially conflicted, yet GLP-compliant, data from the chemical’s manufacturer. It is incomprehensible to me that Conrad and Becker (2011) assert that a financial conflict of interests should not be a criterion in determining the financial independence of researchers (and therefore the reliability of results). A financial conflict of interests exists as soon as there is a link between a researcher and a monetary value. It does not signify unethical behavior, but it does warn of that possibility. Scientists should be reassured—not upset, as Conrad and Becker (2011) claim—if financial conflict of interests was the lead criteria to assess data quality. Conrad and Becker’s substitute criterion—disclosure of financial conflict of interests—becomes useless with their other recommendation to accept the data of financially conflicted scientists. Conrad and Becker (2011) failed to mention the independent and consistent reviews that all but prove that sponsorship of science by the pharmaceutical industry produces results more financially favorable to them than those of financially independent science, and several reviews of toxicity studies of petrochemicals reach the same conclusion (Bekelman et al. 2003; Fagin et al. 1999; Swaen and Meijers 1988; vom Saal and Hughes 2005). Repeatedly Conrad and Becker (2011) urge regulators to accept GLP as a key criterion determining data reliability (the ability to predict actual toxicities). The Organisation for Economic Co-operation and Development (OECD) creates toxicity study guidelines (OECD 2011) featuring GLP, which are adopted worldwide by regulators. These OECD regulatory test protocols are stuck in the age of the light microscope, test a narrow and unrealistic portion of the dose–response curve and relatively few end points, mostly fail to test toxicity during vulnerable development, and kill the animals being tested before most diseases develop (a human equivalent of ~ 60 years). Society should not accept that the OECD GLP protocols are better than those developed by independent, curious academics. Therefore, for any common petrochemical, readers should compare in depth the independent toxicity findings via PubMed and the OECD GLP alleged safe exposure level, which Conrad and Becker (2011) promote. Conrad and Becker (2011) proposed that industry be allowed to continue to influence research, although they would discount studies for which a sponsor owns the results. Journals seem to prefer the simplicity and finality of forbidding outsider control of a researcher’s data. Finally, Conrad and Becker (2011) (compared with Becker et al. 2009) gave lukewarm support to traditional journal peer review and publication, but they continue to question its value, claiming instead that peer review by government regulatory agencies is of better quality. However, such a criterion would simply reinforce these agencies’ current use of these financially conflicted data in determining risk assessment outcome. It would be better if risk assessment relied on traditional peer review, which is science’s most fundamental tool for ensuring reliable data. False-negative error is more consequential than false-positive error.

Comparison of experimentally determined and mathematically predicted percutaneous penetration rates of chemicals

The aim of the study was to evaluate the predictive potential of three different mathematical models for the percutaneous penetration of industrial solvents with respect to our experimental data. Percutaneous penetration rates (fluxes) from diffusion cell experiments of 11 chemicals were compared with fluxes predicted by mathematical models. The chemicals considered were three glycol ethers (2-butoxyethanol, diethylene glycol monobutyl ether and 1-ethoxy-2-propanol), three alcohols (ethanol, isopropanol and methanol), two glycols (ethylene glycol and 1,2-propanediol), one aromatic hydrocarbon (toluene) and two aromatic amines (aniline and o-toluidine). For the mathematical prediction of fluxes, models described by Fiserova-Bergerova et al. (Am J Ind Med 17:617-635 1990), Guy and Potts (Am J Ind Med 23:711-719 1993) and Wilschut et al. (Chemosphere 30:1275-1296 1995) were used. The molecular weights, octanol-water partition coefficients (LogP) and water solubilities of the compounds were obtained from a database for modelling. The fit between the mathematically predicted and experimentally determined fluxes was poor (R(2) = 0.04-0.29; linear regression). The flux differences ranged up to a factor of 412. For 4 compounds, the Guy and Potts model showed a closer fit with the experimental flux than the other models. The Wilschut et al. model showed a lower flux difference for 4 compounds as compared to experimental data than the models of Fiserova-Bergerova et al. and Guy and Potts. The Fiserova-Bergerova et al. model showed for 3 compounds a lower flux difference to experimental data than the other models. This study demonstrates large differences between mathematically predicted and experimentally determined fluxes. The percutaneous penetration as determined in diffusion cell experiments may be considerably overestimated as well as underestimated by mathematical models. Although the number of compounds in our comparison study is small, the results point out that none of the mathematical model has significant advantages.

Carbon Black

Carbon Black

Oil and Water

Oil and Water

A Rare Cause of Dysphagia: Malignant Pleural Mesothelioma in the Posterior Mediastinum

A 69-year-old man presented to the emergency room with dysphagia and vomiting. A computed tomographic scan revealed a posterior mediastinal mass surrounding the lower portion of the esophagus. Endoscopic examination demonstrated narrowing of the lower esophagus without malignant mucosal lesions. Thoracoscopic biopsies of the mediastinal mass failed to yield a pathologic diagnosis. The hyaluronic acid concentration in the left pleural effusion was remarkably high (755 mg/L), which is a finding strongly suggestive of malignant mesothelioma. Four months after the initial admission, a subcutaneous nodule was found in the left chest wall and a biopsy was taken. The histopathologic and immunohistochemical findings of the biopsy were consistent with the diagnosis of pleural malignant mesothelioma.

Emergency responder health: what have we learned from past disasters?

As the Deepwater Horizon disaster unfolds in the Gulf of Mexico, public health practitioners are having a sinking deja vu feeling. Once again, environmental disaster has struck, and tens of thousands of emergency responders—some professionals, but many more volunteers—have swung into action, potentially risking their health as they work to clean up the worst oil spill in U.S. history. Veterans of similar disasters are wondering if historical lessons learned can help keep the damage to a bare minimum. But a paucity of hard data on emergency responder health makes it difficult even to ask the right questions. “Emergency responders have not been adequately studied,” says Gina Solomon, codirector of the occupational and environmental medicine residency and fellowship program at the University of California, San Francisco, and a senior scientist with the Natural Resources Defense Council. “They tend to be ignored.” Professional emergency responders such as firefighters may not put much emphasis on health effects studies. “They are going to do what they need to do regardless of their own safety,” says Don Donahue, executive director of the Center for Health Policy & Preparedness at the Potomac Institute for Policy Studies, who has firefighters in his extended family. “They have to be a little crazy by definition.” That heroic approach is manna for the people they save, but firefighters may pay a price with disorders such as cancer. Studies of cancers in firefighters have had mixed results, but there is evidence linking this occupation with brain, thyroid, esophageal, bladder, testicular, prostate, and cervical cancers, as well as melanoma and Hodgkin disease (Bates1 and Ma et al.2 are two such studies). Health risks tend to be even greater for the many nonprofessional emergency responders who rush to the scene of crises such as oil spills, terrorist attacks, hurricanes, train derailments, and chemical releases. Those workers often don’t have the training and advanced equipment that protect professional emergency responders to some degree. These and many other factors make it a daunting challenge to protect the health of emergency responders during disasters.

Good Laboratory Practices and Safety Assessments: Another View

In a letter responding to an article by Myers et al. (2009), Becker et al. (2009) claimed that industry’s Good Laboratory Practices (GLP)-compliant studies are superior to traditional academic peer-review in predicting the risk of toxic agents. I have read almost 30,000 experimental, etiologic, and epidemiologic papers (most in part), and it is evident that industry GLP studies do not report the same risks of a chemical when published in peer-reviewed studies from academia. This may be explained by biases in industry experiments and epidemiology, especially in design, due to the financial interests of industry sponsors—some receiving billions of dollars in revenue per chemical each year. For pharmaceuticals, dozens of published reviews show a strong correlation between industry sponsorship and findings of safety; I know of four such strong correlations in studies of industrial chemical risks (Bekelman et al. 2003; Fagin and Lavelle 1999; Swaen and Meijers 1988; vom Saal and Hughes 2005). Becker et al. (2009) relied on a commentary by a former editor at the Nature research journals (Jennings 2006) to claim that peer-review gives inferior data compared with GLP studies. Actually, Jennings (2006) wrote about improving, not abandoning, peer review. He presented data showing that the long-term value of scientific papers in neuroscience (judged by experts) correlates with the quality of the journals in which they were published (based on impact factor). That is a cardinal finding because industry supports various journals and their scientific associations, but their GLP studies are rarely published in high-quality journals (again, based on my readings). Evidently, industry’s GLP data are not reliable enough to publish, while financial independence of authors and editors, as well as peer review, are markers of good quality data. Since the widespread experimental testing frauds at Industrial Bio-Test Laboratories (Schneider 1983) and Craven Laboratories (U.S. Environmental Protection Agency 1994), which generated the GLP reforms, industry has issued oceans of GLP-compliant studies for submission to regulatory agencies. Few are submitted for publication, but almost all (in my experience) are submitted to journals that publish many industry-sponsored studies. Critically, industry and their regulatory agencies took the opportunity proferred by the requirement to comply with GLP to exclude almost all academic high-quality, non-GLP studies from risk assessments of existing chemicals (and the toxicity of new agents are primarily evaluated by the parties who want to sell it). For existing chemicals, I have always found that the effective toxicity doses in regulatory (GLP) studies are higher than those in the peer-reviewed literature, for several end points. It is important for individuals who value the contributions that science makes to society (reliable data)—or those who are cautious about toxicity of low-dose and cocktail agents that may affect biochemical signals, especially during development—to continue lobbying public agencies to incorporate academia’s peer-reviewed studies and to use disclosure of financial interests to give appropriate credence to industry’s data in chemical risk assessments. I also call on independent academics to be less competitive and make their methods and data more freely available.

Inter- and intraobserver variation between radiologists in the detection of abnormal parenchymal lung changes on high-resolution computed tomography

BACKGROUND AND OBJECTIVES:Radiological and histological evaluations are affected by subjective interpretation. This study determined the level of inter- and intraobserver variation among radiologists for detection of abnormal parenchymal lung changes on high resolution computed tomography (HRCT).METHODS:HRCT images of 65 patients known to have systemic lupus erythematosus (with clinical pulmonary involvement) were retrospectively reviewed by four nonthoracic radiologists (two with expertise in magnetic resonance [MR] and two general radiologists). Each radiologist read the scans twice, with an interval between readings of at least 6 months. The interobserver variation among the first and second readings of the four radiologists and the intraobserver variation of each radiologist's two readings were assessed by the kappa statistic.RESULTS:There was good agreement between the first and second readings of each radiologist. There was moderate agreement between the two readings of one MR radiologist (kappa=0.482); the other three radiologists had kappa values that were good to excellent (0.716, 0.691, and 0.829). There was a clinically acceptable level of interobserver variability between all radiologists. The agreement was fair to moderate between the MR radiologist and the other observers (kappa range: 0.362-0.519) and moderate to good between the other three radiologists (0.508-0.730).CONCLUSION:The interpretation of imaging findings of abnormal parenchymal lung changes on HRCT is reproducible and the agreement between general radiologists is clinically acceptable. There is reduced agreement when the radiologist is not involved on a regular basis with thoracic imaging. Difficult or indeterminate cases may benefit from review by a chest radiologist.

In Megakaryocytic Differentiation, the Aryl Hydrocarbon Receptor (AhR) Transcription Factor Regulates Hes1 Expression and Megakaryocytic Polyploidization.

Abstract 2519Poster Board II-496Understanding the mechanisms underlying megakaryocytic (Mk) differentiation and maturation is vital to the discovery of novel approaches to treating Mk and platelet disorders such as thrombocytopenia, megakaryoblastic leukemia, and thrombocythemia. The number of platelets released is proportional to the amount of DNA present in a given Mk, so insights into the molecular basis of Mk polyploidization could inspire improved ex vivo culturing methods to promote Mk commitment, expansion, and differentiation, leading to improved autologous transfusion protocols to offset thrombocytopenia associated with HSC transplants following high-dose chemotherapy or MDS progression. Microarray analyses on ex vivo Mk-differentiated primary human CD34+ cells showed that mRNA levels of the Aryl Hydrocarbon Receptor (AhR) increased during Mk differentiation and was elevated 4–6 fold in Mks compared to isogenic granulocytic cultures. These data were further confirmed by quantitative(Q)-RT-PCR analysis of differentiating Mks derived from primary human CD34+ cells as well as from CHRF cells (human megakaryoblastic leukemia). We have shown that CHRF cells are a valid model of human Mk differentiation (Fuhrken PG et al. Exp Hematol, 2007; 35:476–489). Thus, we hypothesized that AhR may act as a novel Mk transcription factor, possibly by influencing or regulating Mk polyploidization. Known as a “toxin sensor”, AhR is involved in the mechanism of action of environmental toxins, likely by altering cell cycle regulation. Epidemiological studies of toxic waste spills and Vietnam veterans suggest that exposure to known AhR ligands may result in increased platelet counts proportional to dioxin exposure level (Webb K et al. Am J Ind Med, 1987;11:685–691, Michalek JE Arch Environ Health, 2001; 56:396–405). These studies offer the intriguing possibility that AhR activation modulates megakaryocyte differentiation and/or platelet production. Interestingly, AhR influences the differentiation of other myeloid lineages including monocytes (Hayashi S et al. Carcinogenesis, 1995; 16:1403–1409) and is upregulated after leukocyte activation (Crawford RB et al. Mol Pharmacol, 1997; 52:921–927). Western blot analyses determined that although initially expressed in both the cytoplasm and nucleus, AhR became solely nuclear in differentiating CHRF cells. EMSA analysis using CHRF nuclear extracts demonstrated that AhR binding to a consensus binding sequence increased as megakaryopoiesis progressed (n=3). Increased AhR-DNA binding during CHRF Mk differentiation correlated with 4.6-fold increased mRNA expression of the AhR transcriptional target Hes1 (n=3, p<0.005), a known cell-cycle regulator and mediator of notch signaling. In order to examine the functional role of AhR in megakaryopoiesis, we generated 3 independent AhR knockdown (KD) CHRF cell lines. Depending on the day of culture, AhR-KD CHRF cell lines differentiated into Mk cells expressed 2-3 fold less AhR mRNA (n=3; p<0.02), 40–60% less AhR protein (n=3), 2.7 times less Hes1 mRNA (n=3; p=0.018), displayed Mk-ploidy distributions shifted towards lower ploidy classes, and were incapable of reaching higher ploidy classes (i.e., ≥32n) seen in control cells. Ploidy levels on day 7 (maximal ploidy in control cells) were 3-fold lower in AhR-KD CHRF cells (n=3; p=0.012 or p=0.005 depending on KD cell line). AhR KD resulted in increased DNA synthesis of low ploidy (<8n; n=3; p<0.05) without influencing apoptosis (n=3, p=0.37). These data suggest that AhR may regulate the cell cycle differently in Mks compared to other cell types, where loss of AhR results in cell cycle blockage and increased apoptosis. As such, AhR deregulation provides a mechanistic explanation for chemical-induced thrombocytopenia, including chemotherapy, and suggests that AhR agonists may provide novel therapies for megakaryoblastic leukemia. AhR-mediated expression of Hes1, an established regulator of the Notch signaling pathway, provides a novel molecular model of endomitotic entry and Mk polyploidization; in drosophila, Notch cell-cycle regulation controls the initial switch toward endomitosis. Disclosures:No relevant conflicts of interest to declare.

Carbon black and lung cancer—testing a novel exposure metric by multi‐model inference

In a recent analysis of a UK cohort Sorahan and Harrington [2007: Am J Ind Med 50: 555-564] assessed the most recent 15 years of exposure ("lugging") to support their hypothesis that carbon black acts as a late stage lung carcinogen. We tested this metric in a German cohort of 1,528 carbon black workers. We used a multi-model Cox regression approach (720 models) to explore the impact of duration and cumulative exposure to carbon black "lugged" by 0, 5, 10, 15, and 20 years. This approach covered four sub-cohorts, including an inception cohort, different exposure scenarios and varying combinations of confounders. Seven hundred nineteen models returned negative coefficients. Only one model estimated a small positive, but clearly non-significant coefficient (P = 0.8). Despite extensive searching, no exposure scenario suggested an adverse effect of "lugged" carbon black exposure on lung cancer mortality. Our analysis does not support the hypothesis of carbon black being a late stage carcinogen.

Relation of Adult-Onset Asthma to Coronary Heart Disease and Stroke

Asthma was associated with atherosclerotic disease in several studies, with evidence that this association may be limited to women. However, most previous studies failed to account for the heterogeneity of asthma subtypes. We previously reported increased carotid intima-medial thickness in women with adult-onset asthma. In this study, the association of adult- and child-onset asthma with incident coronary heart disease (CHD) and stroke were examined. Subjects were classified according to self-report of physician-diagnosed asthma and age of asthma onset. Cox proportional hazards models were used to test the association of adult- and child-onset asthma with incident CHD and stroke, testing for gender interaction. Subanalysis was also performed using only never smokers. Women with adult-onset asthma experienced a 2-fold increase in incident CHD and stroke that was independent of other risk factors, including smoking, body mass index, and physical activity, and persisted when analysis was restricted to never smokers. No significant association was found in women with child-onset asthma or in men. In conclusion, adult-onset asthma may be a significant risk factor for CHD and stroke in women, but not men.

Proceedings of the Summit on Environmental Challenges to Reproductive Health and Fertility: executive summary

The 2007 Summit on Environmental Challenges to Reproductive Health and Fertility convened scientists, health care professionals, community groups, political representatives, and the media to hear presentations on the impact of environmental contaminants on reproductive health and fertility, and to discuss opportunities to improve health through research, education, communication, and policy. Environmental reproductive health focuses on exposures to environmental contaminants, particularly during critical periods of development, and their potential effects on future reproductive health, including conception, fertility, pregnancy, adolescent development, and adult health. Approximately 87,000 chemical substances are registered for commercial use in the United States, with ubiquitous human exposures to environmental contaminants in air, water, food, and consumer products. Exposures during critical windows of susceptibility may result in adverse effects with lifelong and even intergenerational health impacts. Effects can include impaired development and function of the reproductive tract and permanently altered gene expression, leading to metabolic and hormonal disorders, reduced fertility and fecundity, and illnesses such as testicular, prostate, uterine, and cervical cancers later in life. This executive summary reviews effects of pre- and postnatal exposures on male and female reproductive health, and provides a series of recommendations for advancing the field in the areas of research, policy, health care, and community action.

Proceedings of the Summit on Environmental Challenges to Reproductive Health and Fertility: executive summary

The 2007 Summit on Environmental Challenges to Reproductive Health and Fertility convened scientists, health care professionals, community groups, political representatives, and the media to hear presentations on the impact of environmental contaminants on reproductive health and fertility, and to discuss opportunities to improve health through research, education, communication, and policy. Environmental reproductive health focuses on exposures to environmental contaminants, particularly during critical periods of development, and their potential effects on future reproductive health, including conception, fertility, pregnancy, adolescent development, and adult health. Approximately 87,000 chemical substances are registered for commercial use in the United States, with ubiquitous human exposures to environmental contaminants in air, water, food, and consumer products. Exposures during critical windows of susceptibility may result in adverse effects with lifelong and even intergenerational health impacts. Effects can include impaired development and function of the reproductive tract and permanently altered gene expression, leading to metabolic and hormonal disorders, reduced fertility and fecundity, and illnesses such as testicular, prostate, uterine, and cervical cancers later in life. This executive summary reviews effects of pre- and postnatal exposures on male and female reproductive health, and provides a series of recommendations for advancing the field in the areas of research, policy, health care, and community action.

Total imprecision of exposure biomarkers: Implications for calculating exposure limits. Grandjean P, Budtz‐Jørgensen E. Am J Ind Med. 2007;50:712–719.

Total imprecision of exposure biomarkers: Implications for calculating exposure limits. Grandjean P, Budtz‐Jørgensen E. Am J Ind Med. 2007;50:712–719.

Optimizing BeLPT criteria for beryllium sensitization

The beryllium lymphocyte proliferation test (BeLPT) is used to identify persons sensitized to beryllium. ATSDR convened an expert panel of physicians and scientists in April 2006 to discuss this test and to consider what BeLPT test results actually establish beryllium sensitization. The three criteria proposed by panel members were (1)one abnormal result, (2)one abnormal and one borderline result, and (3)two abnormal results. Complete algorithms were developed for each of the three proposed criteria. Using single-test outcome probabilities developed by Stange et al. [2004. Am J Ind Med 46:453-462], we calculated and compared the sensitivity, specificity, and positive predictive values (PPVs) for each set of criteria. The overall sensitivity and specificity of the three criteria were similar. When the criteria required confirmation of an abnormal result the PPV was higher--whether the requirement was satisfied by a borderline result, or only by another abnormal result. Confirmation also reduced the likelihood of false positives. The differences between the three criteria decreased as the prevalence of sensitization increased. A single unconfirmed abnormal is usually insufficient to establish sensitization for an apparently healthy person. When the prevalence of beryllium sensitization in a group is high, however, even a single abnormal BeLPT can be a strong predictor.

Methylmercury and the Developing Brain

We reported that prenatal exposure to methylmercury causes cognitive impairment in an estimated 316,588 children born in the United States each year, costing this nation $8.7 billion annually in lost productivity (Trasande et al. 2005). Each year, this exposure also causes an estimated 1,566 cases of mental retardation (Trasande et al. 2006). The principal (70%) source of the mercury that enters the bodies of American children is combustion of coal in electricity-generating plants. In their reanalysis of our data, Griffiths et al. (2007) made a series of incorrect judgments and poorly considered assumptions, each of which diminishes the import of our findings. We note the following errors in their analysis: First, Griffiths et al. (2007) incorrectly used a linear model to relate cognitive function to prenatal methylmercury exposure, despite the National Research Council’s (NRC) clear finding that a logarithmic model provides a better statistical fit. The NRC, in their examination of the Faroe Islands cohort study, the study on which they place greatest reliance, stated that “[b]ecause these calculations necessitate extrapolating to estimate the mean response at zero exposure level,” logarithmic models “lead to lower estimates of the Benchmark Dose (BMD) than linear or K-power models” (NRC 2000, p. 294). Recent analyses of early childhood lead exposure further corroborate the validity of logarithmic models in representing subclinical dose–response relationships of neuro-developmental injury (Canfield et al. 2003). Second, Griffiths et al. (2007) unwisely based their analysis on potentially biased data from the Seychelles cohort study. By contrast, our model (Trasande et al. 2005), like that of the NRC, is based primarily on Faroes data. We chose not to use Seychelles data because of concern that the tests of neurobehavioral function used there were not well validated for a non-American population and therefore may not have been sensitive to detect cognitive impairment (Landrigan and Goldman 2003). Another major potential source of bias in the Seychelles study, not acknowledged by Griffiths et al. (2007), is that it fails to consider the potentially beneficial nutrients found in the fish-based diet of the Seychelles. These nutrients, omega-3 fatty acids in particular, may partially offset the toxicity of methylmercury. Indeed, if maternal fish intake is taken into account in the Seychelles cohort, as recently was done, the estimate of methylmercury toxicity increases (Budtz-Jorgensen et al. 2007). Griffiths et al. (2007) cited previous meta-analyses of the Faroes, Seychelles, and New Zealand studies by Ryan (2005) in applying IQ decrements of 0.13–0.18 points/ppm hair mercury, but these are likely underestimates, and further invalidate the analysis of Griffiths et al. Third, in attributing mercury deposition to sources of emission, Griffiths et al. (2007) relied inexplicably and without justification on a mathematical model that posits that only 16% of deposits are attributable to American sources. They ignored empiric data from the U.S. Environmental Protection Agency (EPA)-sponsored Steubenville study, which found that 80–90% of mercury emissions deposit within 30–50 miles of the source (U.S. EPA 2007); and from the Electric Power Research Institute, which estimated that 30% of mercury deposits are attributable to American sources (Seigneur et al. 2004). Fourth, Griffiths et al. (2007) incorrectly assumed that reductions in mercury emissions from power plants do not result in any reduced levels of fish contamination until after 15 years. This is not correct. Reductions in power-plant emissions in 2008 will, in fact, begin immediately to minimize methylmercury body burden among children born to women in 2008, and the degree of reduction will increase further in subsequent years, perhaps through 2038, thus reducing the number of children damaged, the severity of the prenatal brain damage in these children, and the resulting economic burden. Finally, Griffiths et al. (2007) incorrectly based their estimate of the economic value of a child’s social productivity on the 1992 Current Population Survey rather than on the currently available 2005 data set. This miscalculation substantially underestimates the economic impact of methylmercury on the developing brain. Viscusi and Aldy (2004) estimated that this value is currently on the order of $4–9 million/child, a value far greater than that used by Griffiths et al., and greater even than our estimate.

Clock Gene Expression in the Murine Gastrointestinal Tract: Endogenous Rhythmicity and Effects of a Feeding Regimen

Based on observations that the gastrointestinal tract is subject to various 24-hour rhythmic processes, it is conceivable that some of these rhythms are under circadian clock gene control. We hypothesized that clock genes are present in the gastrointestinal tract and that they are part of a functional molecular clock that coordinates rhythmic physiologic functions. The effects of timed feeding and vagotomy on temporal clock gene expression (clock, bmal1, per1-3, cry1-2) in the gastrointestinal tract and suprachiasmatic nucleus (bmal, per2) of C57BL/6J mice were examined using real-time polymerase chain reaction and Western blotting (BMAL, PER2). Colonic clock gene localization was examined using immunohistochemistry (BMAL, PER1-2). Clock immunoreactivity was observed in the myenteric plexus and epithelial crypt cells. Clock genes were expressed rhythmically throughout the gastrointestinal tract. Timed feeding shifted clock gene expression at the RNA and protein level but did not shift clock gene expression in the central clock. Vagotomy did not alter gastric clock gene expression compared with sham-treated controls. The murine gastrointestinal tract contains functional clock genes, which are molecular core components of the circadian clock. Daytime feeding in nocturnal rodents is a strong synchronizer of gastrointestinal clock genes. This synchronization occurs independently of the central clock. Gastric clock gene expression is not mediated through the vagal nerve. The presence of clock genes in the myenteric plexus and epithelial cells suggests a role for clock genes in circadian coordination of gastrointestinal functions such as motility, cell proliferation, and migration.

Re-assessment of the influence of polymorphisms of phase-II metabolic enzymes on renal cell cancer risk of trichloroethylene-exposed workers

Individual differences in susceptibility to trichloroethylene-induced nephrocarcinogenicity may be conferred by genetic polymorphisms of glutathione S-transferases (GST), because enzymes of this group are pivotal for the metabolic activation of trichloroethylene. Because of a potential involvement of N-acetylation in the detoxication of reactive trichloroethylene metabolite(s) to N-acetyl-cysteine derivatives, polymorphisms of the NAT2 gene may also be relevant. The primary collective used for a re-investigation of these questions was that of a hospital-based case-control study by Brüning et al. (Am J Ind Med 43:274-285, 2003) of 134 renal cell cancer cases (20 cases exposed to trichloroethylene) and 401 matched controls. Genetic polymorphisms of GSTT1, GSTM1, GSTP1 and NAT2 were studied. Additional control collectives of non-diseased persons were used for comparison of allele frequencies. No genetic influences on the development of renal cancer due to trichloroethylene were apparent, related to the deletion polymorphisms of GSTT1 and GSTM1, as well as to the NAT2 rapid/slow acetylator states. However, renal cell cancer cases displayed a somewhat higher proportion of the homozygous GSTP1 313A wild type (GSTP1*A), although this was not statistically significant (chi(2) test: P=0.1071, when using only the original controls of Brüning et al. (2003); P=0.0781 with inclusion of the additional controls). The re-investigation does not confirm the working hypothesis of an influence of the deletion polymorphisms of the glutathione S-transferases GSTT1 and GSTM1 on renal cell cancer development due to high occupational exposures to trichloroethylene.

Ozone and Semen Quality: Berhane and Sokol Respond

We thank Bonde for his interest in our article (Sokol et al. 2006) and for drawing to our attention the literature on the effects of the welding occupation on male fertility. Although we agree with Bonde that the findings in the occupational studies he cited, for the most part, do not show a correlation between welding and abnormal semen parameters, one of his studies does report such an association (Bonde 1990), as does an article by Mortenson (1988). We find these data intriguing and puzzling, but we also would like to make the following points. First, our study (Sokol et al. 2006) was population based and hence not directly comparable to the occupational studies. Although our study directly investigated the effects of ozone, albeit from the ambient point of view and not via personal monitoring of exposure, the evidence from the occupational studies (Bonde 1990; Mortenson 1988) is an indirect and implied one. In these studies, direct O3 exposure information is not provided. In one of the negative studies (Hjollund et al. 1998), no differences in urine concentrations for the trace metals associated with welding were detected between welders and nonwelders, suggesting that “the negative results could be due to generally low exposure of the study base” (Hjollund et al. 1998). The longitudinal design of our study (Sokol et al. 2006) gave us the opportunity to examine within-subject (over time) effects of O3 on male fertility in a sample that guarantees validity of the asymptotic inferences we made from the data. The modeling techniques we used in the analysis have become fairly standard in analysis of longitudinal data such as ours; these techniques properly account for the within-subject correlation in the repeated measures for each subject. It is very unlikely that the O3 findings are artifacts of our modeling approach. Finally, we carefully examined the potential confounding effects of weather, seasonality, and long-term time trends, and the O3 findings were robust to their inclusion in the models. Moreover, the O3 effects were robust to inclusion of other pollutants in the model. That said, we readily acknowledge the excellent point that Bonde raised with respect to indoor–outdoor ratio of O3 exposure and possible misclassification of exposure due to the ambient nature of our exposure assignment. Ideally, we would have liked to assign direct personal exposure values or use a microenvironmental model (Navidi and Lurman 1995) to assign personal exposure values according to time–activity patterns, but this was not possible because of the retrospective nature of our study. However, we believe that the longitudinal design of our study (Sokol et al. 2006) gives us more confidence in the results, assuming consistent within-subject time–activity patterns. We hope that future research will replicate our study (Sokol et al. 2006) in other locations around the world, preferably allowing for personal monitoring of exposure. We also hope that occupational studies will focus on direct assessment of O3 exposure to allow for direct comparisons with population-based studies whenever possible. Finally, we acknowledge that our epidemiologic findings of strong associations only add to the evidence in support of O3 effects on male fertility and but do not necessarily show causation.

Stopping Stress at Its Origins: Addressing Working Conditions

HomeHypertensionVol. 49, No. 5Stopping Stress at Its Origins: Addressing Working Conditions Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBStopping Stress at Its Origins: Addressing Working Conditions Sean Collins Paul Landsbergis Nicholas Warren Anthony D. LaMontagne Sean CollinsSean Collins University of Massachusetts Lowell, Lowell, Mass Search for more papers by this author Paul LandsbergisPaul Landsbergis Mount Sinai School of Medicine, New York, NY Search for more papers by this author Nicholas WarrenNicholas Warren University of Connecticut Health Center, Farmington, Conn Search for more papers by this author Anthony D. LaMontagneAnthony D. LaMontagne University of Melbourne, Melbourne, Australia Search for more papers by this author Originally published5 Mar 2007https://doi.org/10.1161/HYPERTENSIONAHA.107.088633Hypertension. 2007;49:e33Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: March 5, 2007: Previous Version 1 To the Editor:A significant volume of research relates occupational stress to cardiovascular disease.1 Although a variety of methods exists for measuring occupational stress, a consistent feature of these measurements is a focus on environmental and work organization origins as opposed to individual characteristics and responses. This paradigm comes from occupational health with identifying exposure sources as distinct from measuring biological and/or behavioral response to exposure. Eliminating exposure is the preferred prevention, and personal protective equipment is an acceptable alternative when no other option exists. We equate job redesign with eliminating exposure and stress management to a personal protective equipment approach to occupational stress.2We agree with Milani and Lavie3 regarding the importance and global impact of stress-related conditions; however, we do differ on the meaning of “stop stress at its origins.” We also disagree with calling exposure to work environment sources of stress as “lifestyle” stressors. We applaud the work praised by Milani and Lavie3 and performed by Lucini et al4 for furthering our understanding of autonomic dysregulation as a consequence of work stress and for testing the effectiveness of stress management. The relationship between environmentally measured job stressors and autonomic dysregulation has been documented,5 and the use of heart rate variability as a measurement strategy for assessing individual response and cardiac disease risk is recommended.The best available evidence, based on several international job stress intervention reviews, shows that the most effective interventions to mitigate job stress and related adverse effects on health is a mixed strategy in which consideration is given to both work-directed and person-directed measures.2 Put another way, this means a combination of both primary and secondary prevention: job redesign coupled with “personal protective equipment” in the form of stress management programs.6 Stress management might need to precede attempts at job redesign to facilitate effective participatory action-based job redesign programs. Contrary to a behavior-based stress management program, the elimination of environmental sources of stress is more likely to result in lasting, sustainable stress reduction.6 It is unknown whether participants can sustain the practice of stress management programs in the face of ongoing job stress. Few stress management studies had a follow-up time >6 months, and approximately one third of participants fail to learn the techniques.6 In contrast, interventions that use systems approaches (emphasize primary prevention, integrate strategies, and include participation of targeted groups) tend to have longer intervention and evaluation follow-up times, usually on the order of months to years, and are the most effective in addressing both the organizational and individual impacts of job stress.6DisclosuresNone.1 Schnall PL, Belkic K, Landsbergis P, Baker D. The Workplace and Cardiovascular Disease. Occupational Medicine: State of the Art Reviews, vol 15. Philadelphia, PA: Hanley & Belfus, Inc; 2000.Google Scholar2 Karasek RA. An analysis of 19 international case studies of stress prevention through work reorganization using the demand/control model. Bull Sci Technol. 2004; 24: 446–456.CrossrefGoogle Scholar3 Milani RV, Lavie CJ. Stopping stress at its origins. Hypertension. 2007; 49: 268–269.LinkGoogle Scholar4 Lucini D, Riva S, Pizzinelli P, Pagani M. Stress management at the worksite: reversal of symptoms profile and cardiovascular dysregulation. Hypertension. 2007; 49: 291–297.LinkGoogle Scholar5 Collins SM, Karasek RA, Costas K. Job strain and autonomic indices of cardiovascular disease risk. Am J Ind Med. 2005; 48: 182–193.CrossrefMedlineGoogle Scholar6 LaMontagne AD, Shaw A, Ostry A, Louie AM, Keegel T: Workplace Stress in Victoria: Developing a Systems Approach. Melbourne, Australia: Victorian Health Promotion Foundation; 2006.Google Scholar Previous Back to top Next FiguresReferencesRelatedDetails May 2007Vol 49, Issue 5 Advertisement Article InformationMetrics https://doi.org/10.1161/HYPERTENSIONAHA.107.088633PMID: 17339530 Originally publishedMarch 5, 2007 PDF download Advertisement SubjectsPrimary PreventionSecondary Prevention