Wednesday, April 15, 2009

Job Strain and Major Depression

American Journal of Epidemiology 2009 169(9):1085-1091; doi:10.1093/aje/kwp037


Changes in Perceived Job Strain and the Risk of Major Depression: Results From a Population-based Longitudinal Study

JianLi Wang, Norbert Schmitz, Carolyn Dewa and Stephen Stansfeld

Correspondence to Dr. JianLi Wang, Room 127, Heritage Medical Research Building, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1 (e-mail:

Received for publication August 14, 2008. Accepted for publication January 26, 2009.

Major depression is a prevalent mental disorder in the working population. Improving the work environment may reduce the risk of major depression. The authors examined data from the longitudinal cohort of the Canadian National Population Health Survey from 1994–1995 to 2004–2005. Survey participants were classified into 4 groups by changes in job strain status from 1994–1995 to 2000–2001 (no change in low job strain, no change in high job strain, changing from high to low job strain, and changing from low to high job strain). The incidence proportion of major depressive episodes in each of the 4 groups was 4.0%, 8.0%, 4.4%, and 6.9%, respectively. Participants who reported a change from high to low job strain had a risk of major depression similar to those exposed to persistently low job strain. Among those exposed to persistent high job strain, only participants who reported good or excellent health at baseline had a higher risk of major depression, but those who reported fair or poor health did not. Reducing job strain may have positive impacts on the risk of depression. Self-rated health is a strong predictor of depression and plays an important role in the relation between job strain and depression.


BrooklynDodger(s) comment: Job strain is measured by instruments which everyone knows are not perfect. Nevertheless, mental illness is the leading illness cause of time off the job by active employees. High and increasing job strain contribute to a high incidence outcome. Depression can be considered a potentially fatal disease.

Monday, April 13, 2009

An Early Version of the Particle Overload Houdini Hypothesis

Toxicology and Applied Pharmacology
Volume 99, Issue 3, July 1989, Pages 377-383

Contemporary issue in toxicology

Establishing aerosol exposure concentrations for inhalation toxicity studies

Trent R. Lewis*, Paul E. Morrow, Roger O. McClellan, Otto G. Raabe§, Gerald L. Kennedyshort parallel, Bernard A. Schwetzperpendicular, Thomas J. Goehlperpendicular, Joseph H. Roycroftperpendicular and Rajendra S. Chhabraperpendicular

* Division of Biomedical and Behavioral Science, National Institute for Occupational Safety and Health, 4676 Columbia Parkway, Cincinnati, Ohio 452276, USA

Environmental Health Science Center, University of Rochester, Rochester, NY 14642, USA

Lovelace Inhalation Toxicology Research Institute, Albuquerque, New Mexico 87185, USA

§ Laboratory for Energy-Related Health Research, University of California, Davis, California 95616, USA

short parallel Haskell Laboratory, E.I. duPont de Nemours & Co., Newark, Delaware 19711, USA

perpendicular National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA

Received 15 October 1988;
accepted 28 March 1989.
Available online 27 September 2004.


Criteria for the selection of aerosol concentrations to be used in inhalation studies assessing the toxicity and carcinogenicity of chemical substances were discussed by the authors in a meeting sponsored by the National Toxicology Program. Concepts in the design of aerosol inhalation studies emerged from that meeting and are being communicated through this publication. Inhalation studies assessing the toxicity and carcinogenicity of aerosols have often used maximum exposure levels on the basis of technological feasibility. Evidence has now accumulated that the amount of pulmonary burden of deposited particles impacts on particle clearance above some as yet not well-defined exposure concentration. The sequelae are such that lung clearance decreases with increased particulate burden to the point of approaching complete cessation. This paper focuses on the major determinants in establishing maximal aerosol concentrations for use in inhalation toxicity studies with special emphasis on experimental design features to assess lung retention. The subject matter of this paper is a rapidly developing area in terms of knowledge. Accordingly, the contents of this article are intended as guidelines and not as absolute rules for the conduct and interpretation of inhalation exposure studies

BrooklynDodger(s) comment: The problem with the pulmonary overload reduced lung clearance Houdini risk assessment hypothesis, is that something not cleared is causing lung tumors. In a single agent study, the agent would have to prevent its own clearance, although there are likely other conditions which would reduce clearance in a human population. So this is a potency issue, not a toxic potential issue. Although, since the negative control, titanium dioxide, is now carcinogenic, it appears that any old particulate material will cause lung tumors. The Dodger(s) note(s) that Roger McClellen co-authored this from Lovelace, an institution of the DOE, before he left to head CIIT.

Sunday, April 12, 2009

Nanoparticle Research Conducted by Pharma

Volume 259, Issue 3, 17 May 2009, Pages 140-148
Retrospective analysis of 4-week inhalation studies in rats with focus on fate and pulmonary toxicity of two nanosized aluminum oxyhydroxides (boehmite) and pigment-grade iron oxide (magnetite): The key metric of dose is particle mass and not particle surface area
Jürgen PauluhnCorresponding Author Contact Information, a, E-mail The Corresponding Author

aInstitute of Toxicology, Bayer Schering Pharma, Department of Inhalation Toxicology, Building no. 514, 42096 Wuppertal, Germany


This paper compares the pulmonary toxicokinetics and toxicodynamics of three different types of poorly soluble dusts examined in repeated rat inhalation bioassays (6 h/day, 5 days/week, 4 weeks). In these studies the fate of particles was studied during a 3–6-month postexposure period. This retrospective analysis included two types of aluminum oxyhydroxides (AlOOH, boehmite), high purity calcined, and agglomerated nanosized aluminas of very low solubility with primary isometric particles of 10 or 40 nm, and synthetic iron oxide black (Fe3O4 pigment grade). Three metrics of dose (actual mass concentration, surface area concentration, mass-based lung burden) were compared with pulmonary toxicity characterized by bronchoalveolar lavage. The results of this analysis provide strong evidence that pulmonary toxicity (inflammation) corresponds best with the mass-based cumulative lung exposure dose. The inhalation study with a MMAD of ≈0.5 μm yielded a higher pulmonary dose than MMADs in the range of 1–2 μm, a range most commonly used in repeated exposure inhalation studies. Hence, a key premise for the dosimetric adjustment across species is that comparable lung tissue doses should cause comparable effects. From that perspective, the determination of mass-based pulmonary lung burdens appears to be amongst the most important and critical nominator of dose and dose-related pulmonary toxicity.

Keywords: Nanoparticles; Repeated inhalation exposure; Disposition; Respirability; Clearance; Aggregates; Dose metric; Pulmonary toxicity; Dosimetry


BrooklynDodger(s) comment: Big Pharma is turning its attention to nanoparticle toxicity by inhalation. Unfortunately, and maybe by design, the exposure levels and the effect responses didn't make it into the abstract. The Dodger(s) expect(s) that iron oxide would be the more potent inflammatory agent.

Saturday, April 11, 2009

More Nanoparticle Toxicity

Toxicology Letters Volume 186, Issue 3, 8 May 2009, Pages 152-159

Comparing fate and effects of three particles of different surface properties: Nano-TiO2, pigmentary TiO2 and quartz
Ben van Ravenzwaay, a, , Robert Landsiedela, Eric Fabiana, Silke Burkhardta, Volker Straussaa
aBASF Product Safety, BASF SE, GV/T - Z470, D-67056 Ludwigshafen, Germany
and Lan Ma-Hock

The fate of nano-TiO2 particles in the body was investigated after inhalation exposure or intravenous (i.v.) injection, and compared with pigmentary TiO2 and quartz. For this purpose, a 5-day inhalation study (6 h/day, head/nose exposure) was carried out in male Wistar rats using nano-TiO2 (100 mg/m3), pigmentary TiO2 (250 mg/m3) and quartz dust DQ 12 (100 mg/m3). Deposition in the lung and tissue distribution was evaluated, and histological examination of the respiratory tract was performed upon termination of exposure, and 2 weeks after the last exposure. Broncho-alveolar lavage (BAL) was carried out 3 and 14 days after the last exposure. Rats were also injected with a single intravenous dose of a suspension of TiO2 in serum (5 mg/kg body weight), and tissue content of TiO2 was determined 1, 14 and 28 days later.
The majority of the inhaled nano-TiO2 was deposited in the lung. Translocation to the mediastinal lymph nodes was also noted, although to smaller amounts than following inhalation of pigmentary TiO2, but much higher amounts than after exposure to quartz. Systemically available nano-TiO2, as simulated by the i.v. injection, was trapped mainly in the liver and spleen. The (agglomerate) particle size of lung deposited nano-TiO2 was virtually the same as in the test atmosphere. Changes in BAL fluid composition and histological examination indicated mild neutrophilic inflammation and activation of macrophages in the lung. The effects were reversible for nano- and pigmentary TiO2, but progressive for quartz. The effects observed after 5-day inhalation exposure to nano-TiO2 were qualitatively similar to those reported in sub-chronic studies.
Keywords: Nano-TiO2; Quartz DQ 12; Surface area; Surface reactivity; Distribution; Toxic effects

BrooklynDodger(s) comment: Nano gets you funded these days. While some worry about nano coming, nano is already here in the form of nano titanium dioxide, nano carbon nanotubes and other high tech carbon black, and have been here long enough to cause cancer in the form of diesel particulate matter. Nano titanium dioxide is generally recognized to cause cancer in rats. Silica is generally recognized to cause caner in rats and in people, and to be more potent in people.

In this system, 5 days at 100 mg/m3 of silica or nano titanium dioxide, cause mild neutrophyllic inflammation and activation of macrophage. For titanium dioxide it appeared reversible, for silica progressive. The TLV for silica, which is feasibility influenced, is now 0.025 mg/m3.

Friday, April 10, 2009

Mounting Evidence for Diesel Engine Emission Health Hazards

Non-cancer health effects of diesel exhaust: A critical assessment of recent human and animal toxicological literature
Authors: Thomas W. Hesterberg a; Christopher M. Long b; William B. Bunn a; Sonja N. Sax b; Charles A. Lapin c; Peter A. Valberg b
a Navistar, Inc., Warrenville, Illinois, USA
b Gradient Corporation, Cambridge, Massachusetts, USA
c Lapin & Associates, Glendale, California, USA

Critical Reviews in Toxicology, Volume 39, Issue 3 March 2009 , pages 195 - 227


We reviewed laboratory and clinical studies bearing on the non-cancer health effects of diesel exhaust (DE) published since the 2002 release of the US EPA Health Assessment Document for Diesel Engine Exhaust. We critically evaluated over 100 published articles on experimental research, focusing on their value for predicting the risk of non-cancer health effects in humans exposed to DE. Recent animal studies provide insight into the potential mechanisms underlying observed respiratory and cardiovascular health responses; however, because of Human controlled-exposure studies provide new evidence of lung inflammatory effects and thrombogenic and ischemic effects of inhaled DE, albeit for older-model diesel engines and concentrations that are much higher (~300 μg/m3) than typical ambient or even occupational levels.unrealistically high DE concentrations, the mechanisms elucidated in these studies may not be relevant at lower DE exposure levels. Although larger in number, and suggestive of possible mechanisms for non-cancer health effects at elevated DE levels, interpretation of this recent group of clinical-study findings and laboratory-animal results remains hindered by inconsistencies and variability in outcomes, potentially irrelevant DE-exposure compositions, limitations in exposure protocols and pathways, and uncertainties in extrapolation and generalization. A mechanism of action that allows reliable prediction of adverse health effects at DE-exposure levels typical of the present-day ambient and occupational environment has not emerged. Because of changing diesel-engine technology, inhalation studies using realistic environmental and occupational exposures of new-technology diesel exhaust are of critical importance.
BrooklynDodger(s) comments:
Given the source, Navistar, the conclusion that more evidence is needed to regulate isn't surprising. Certainty deniers will always be able to argue that the concentrations needed to demonstrate toxic potential in small groups of animals and people over a short period of time are "unrealistic." There are two dozen studies of truck drivers and railroad personnel - large enough groups exposed to DPM for a long enough time. These groups suffer excess mortality from lung cancer.

Thursday, April 09, 2009

Houdini Alert - Single Oral Dose Metabolism of Acrylamide

Toxicokinetics of acrylamide in rats and humans following single oral administration of low doses

Eva Katharina Koppa and Wolfgang Dekant, a,
aDepartment of Toxicology, University of Würzburg, Versbacher Straβe 9, 97078 Würzburg, Germany

The rodent carcinogen acrylamide (AA) is formed during preparation of starch-containing foods. AA is partly metabolized to the genotoxic epoxide glycidamide (GA). After metabolic processing, the mercapturic acids N-acetyl-S-(2-carbamoylethyl)-L-cysteine (AAMA), rac-N-acetyl-S-(2-carbamoyl-2-hydroxyethyl)-L-cysteine (GAMA) and rac-N-acetyl-S-(1-carbamoyl-moyl-2-hydroxyethyl)-L-cysteine (iso-GAMA) are excreted with urine. In humans, AAMA can be sulfoxidized to AAMA-sulfoxide. The aim of this study was to assess potential species-differences in AA-toxicokinetics in rats and humans after single oral administration of doses similar to the daily human dietary exposure. Male Fischer 344 rats (n = 5/dose group) were administered 20 and 100 μg/kg b.w. 13C3-AA in deionized water via oral gavage. Human subjects (n = 3/gender) were orally administered 0.5 and 20 μg/kg b.w. 13C3-AA with drinking water. Urine samples were collected in intervals for 96 and 94 h, respectively. Urinary concentrations of 13C3-AAMA, 13C3-GAMA and 13C3-AAMA-sulfoxide were monitored by liquid chromatography-tandem mass spectrometry. The recovered urinary metabolites accounted for 66.3% and 70.5% of the 20 and 100 μg/kg b.w. doses in rats and for 71.3% and 70.0% of the 0.5 and 20 μg/kg b.w. doses in humans. In rats, 13C3-AAMA accounted for 33.6% and 38.8% of dose and 32.7% and 31.7% of dose was recovered as 13C3-GAMA; 13C3-AAMA-sulfoxide was not detected in rat urine. In humans, 13C3-AAMA, 13C3-GAMA and 13C3-AAMA-sulfoxide accounted for 51.7% and 49.2%, 6.3% and 6.4% and 13.2% and 14.5% of the applied dose, respectively. The obtained results suggest that the extent of AA bioactivation to GA in humans is lower than in rodents.

BrooklynDodger(s) comment: Without full text, the Dodger(s) can't tell who funded this, and the abstract isn't clear. For a single dose study, with rats getting gavage and humans drinking water, these differences are not imposing and don't appear to support the "don't worry, be happy" conclusion.

Wednesday, April 08, 2009

Myrcene Carcinogenesis - Another Facet of the Alpha 2 Houdini Risk Assessment

(CAS NO. 123-35-3)

[beta-myrcene is a C10 terpene, 3 double bonds, two of which are conjugated. It's a natural product, essential oil, related to limonene (tested at NTP), turpentine, etc]

[Tested at 1.0 mg/kg and below in rats (all the 1 mg/kg male rats died) and mice of both genders]

In the standard evaluation of the kidney, the incidence of renal tubule adenoma was significantly increased in 0.5 g/kg male rats, and the combined incidences of renal tubule adenoma or carcinoma were significantly increased in 0.25 and 0.5 g/kg males. In both the extended evaluation and the combined standard and extended evaluations, the incidences of renal tubule adenoma and the combined incidences of renal tubule adenoma or carcinoma were significantly increased in the 0.25 and 0.5 g/kg groups of males. The incidences of renal tubule nephrosis (nephrosis) were markedly increased in all dosed groups of both sexes except in 0.25 g/kg females. The incidences of papillary mineralization in 0.25 and 0.5 g/kg males were significantly increased. Significantly increased incidences of nephropathy occurred in dosed females, and the severity was increased in the 0.5 and 1 g/kg males and females. ...

[MICE] ...
The incidences of liver neoplasms were significantly increased in 0.25 and/or 0.5 g/kg males and 0.25 g/kg females. Liver neoplasms included hepatocellular adenoma and hepatocellular carcinoma in males and females and hepatoblastoma in males. The incidences of hepatocellular hypertrophy were significantly increased in 0.5 g/kg males and females, as was the incidence of mixed cell focus in 0.5 g/kg females.
The incidences of bone marrow atrophy and lymph node follicle atrophy in the spleen were significantly increased in 0.5 g/kg females. ..

"Conclusions Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity of β-myrcene in male F344/N rats based on increased incidences of renal tubule neoplasms. There was equivocal evidence of carcinogenic activity of β-myrcene in female F344/N rats based on increased incidences of renal tubule adenoma. There was clear evidence of carcinogenic activity of β-myrcene in male B6C3F1 mice based on increased incidences of liver neoplasms. There was equivocal evidence of carcinogenic activity of β-myrcene in female B6C3F1 mice based on marginally increased incidences of hepatocellular neoplasms.

Administration of β-myrcene induced nonneoplastic lesions in the kidney of male and female rats, nose of male rats, and liver of male and female mice."


BrooklynDodger(s) comment: The competition for the title "Mother" of all Houdini Risk Assessments is stiff, but the alpha-2 hypothesis is in the running. Adopting alpha 2 allowed industry to make the risk of gasoline (and later MBTE) to disappear and thus escape from imposing controls which would be far reaching.

In plain terms, if a chemical causes kidney tumors in male rats only, and the kidney tumors are accompanied by nephropathy in the male rats only (of a particular kind called hyaline droplet), then the tumors are considered to be irrelevant to human risk. That's consensus, although there is a considerable group of alpha-2 deniers (which include the Dodger(s).

Actually, this "morning after the bioassay pill" to abort risk assessment by killing the hazard identification doesn't really apply to gasoline, the subject of another post.

Myrcene is a terpene, non-cyclic C10 hydrocarbon. Actually, it's got a conjugated double bond, an analogy to butadiene. Myrcene dosing produced clear evidence for kidney cancer in male rats and equivocal in females, but nephrophathy in both. And, clear evidence of liver tumors in male mice and equivocal in the females.

So Myrcene ought to be a 2B at IARC and reasonably anticipated at NTP.

Tuesday, April 07, 2009

Moral Panic - Meth Lab Decontamination Compared to Lead

Journal of Occupational and Environmental Hygiene, Volume 6, Issue 3 March 2009 , pages 151 - 156

Residual Methamphetamine in Decontaminated Clandestine Drug Laboratories
Authors: Glen Patrick a; William Daniell b; Charles Treser b
a Washington State Department of Health, Office of Environmental Health Assessments, Olympia, Washington
b Department of Occupational and Environmental Health Sciences, University of Washington, Seattle, Washington

This pilot cross-sectional study examined three previously decontaminated residential clandestine drug laboratories (CDLs) in Washington State to determine the distribution and magnitude of residual methamphetamine concentrations relative to the state decontamination standard. A total of 159 discrete random methamphetamine wipe samples were collected from the three CDLs, focusing on the master bedroom, bathroom, living room, and kitchen at each site. Additional samples were collected from specific non-random locations likely to be contacted by future residents (e.g., door knobs and light switches). Samples were analyzed for methamphetamine by EPA method 8270 for semivolatile organic chemicals. Overall, 59% of random samples and 75% of contact point samples contained methamphetamine in excess of the state decontamination standard (0.1 μ g/100 cm2). At each site, methamphetamine concentrations were generally higher and more variable in rooms where methamphetamine was prepared and used. Even compared with the less stringent standard adopted in Colorado (0.5 μ g/100cm2), a substantial number of samples at each site still demonstrated excessive residual methamphetamine (random samples, 25%; contact samples, 44%). Independent oversight of CDL decontamination in residential structures is warranted to protect public health. Further research on the efficacy of CDL decontamination procedures and subsequent verification of methods is needed.

BrooklynDodger(s) comment: The Dodger(s) would like the see the risk assessment supporting the 0.1 or the 0.5 ug/100 cm2 clearance limit. Limits are easily set when there's no critique. The Dodger(s) note that amphetamines are given to pilots to improve their performance. Back of the envelope: the lead clearance level for floors is 40 ug/ft2 which computes to 40ug/900 cm2 which computes to 9.5 ug/100 cm2. For windowsills the clearance level is about 60 ug. Does anyone seriously believe that cumulative toxic potency of meth is 100 times that of lead?

Monday, April 06, 2009

Mercury Identified as Posing Endocrine Effects

The endocrine effects of mercury in humans and wildlife
Shirlee W. Tan a; Jesse C. Meiller b; Kathryn R. Mahaffey b
a US Environmental Protection Agency, Office of Science Coordination and Policy, Smithsonian Institution's National Zoological Park, Washington, DC, USA
b US Environmental Protection Agency, Office of Science Coordination and Policy, Washington, DC, USA

Critical Reviews in Toxicology, Volume 39, Issue 3 March 2009 , pages 228 - 269

Mercury (Hg) is well studied and research continues as our knowledge of its health risks increases. One expanding area of research not well emphasized to date is the endocrine effects of Hg. This review summarizes the existing literature on the effects of Hg on the endocrine system and identifies gaps in the knowledge. It focuses on the thyroid, adrenal, and reproductive systems, including the accumulation of Hg in the endocrine system, sex differences that are manifested with Hg exposure, reproductive effects in male and female animals including humans, and Hg effects on the thyroid and adrenal systems. We concluded that there are five main endocrine-related mechanisms of Hg across these systems: (a) accumulation in the endocrine system; (b) specific cytotoxicity in endocrine tissues; (c) changes in hormone concentrations; (d) interactions with sex hormones; and (e) up-regulation or down-regulation of enzymes within the steroidogenesis pathway. Recommendations for key areas of research to better understand how the endocrine effects of Hg affect human and wildlife health were developed, and include increasing the amount of basic biological information available about Hg and wildlife species, exploring the role of Hg in the presence of other stressors and chemicals, understanding sublethal and indirect effects of Hg on adverse outcomes, developing better methods to extrapolate effects across species, and understanding the effects of Hg on multiple organ systems following exposure of an animal. Greater inclusion of endocrine endpoints in epidemiological and field studies on humans and wildlife will also advance the research in this area

BrooklynDodger(s) Comment: This review comes from EPA scientists, suggesting some impending regulatory action, or a at least a new risk assessment. You could imaging that mercury effects every organ system in the body, given a plausible mode of action by mucking up all the sulfhydryl groups in all the enzymes and other proteins.

Saturday, April 04, 2009

Who's Getting Hammered?

Sociodemographic Differences in Binge Drinking Among Adults --- 14 States, 2004

Binge drinking, defined in this study as consuming five or more alcoholic drinks on one occasion,* was responsible for 43,731 (54.9%) of the estimated 79,646 alcohol-attributable deaths each year in the United States during 2001--2005. Healthy People 2010 calls for reducing the prevalence of binge drinking among adults from the 16.6% baseline in 1998 to 6.0% (1). An overarching goal of Healthy People is to eliminate health disparities among different segments of the population.§ To assess binge drinking by sex, age group, race/ethnicity, education level, and income level, CDC analyzed data from an optional module of the 2004 Behavioral Risk Factor Surveillance System (BRFSS) survey, the most recent data available on binge drinking prevalence, frequency, and intensity (i.e., the number of drinks consumed per binge episode). This report summarizes the results of that analysis, which indicated that the prevalence of binge drinking was more common among men (24.3%), persons aged 18--24 years (27.4%) and 25--34 years (24.4%), whites (17.5%), and persons with household incomes >$50,000 (17.4%)...

BrooklynDodger(s) comment: This post recognizes a Saturday night during March Madness. With Michigan State playing and winning. BRFSS frequently has the aspect of moral panic. However, in this case it's young white guys; upwards of a quarter of the dudes who report getting hammered report upwards of 4 (likely weekend) parties a month with upwards of 8 drinks. Who knows how CDC controls for underreporting? [Without revealing age, race or gender, the Dodger(s) would certainly shave the Dodger(s) report.] Probably these guys drive home (or to the next party) too fast and without their seatbelt.