Rachael M. Jones

Benzene exposure and risk of non-Hodgkin lymphoma.

Exposure to benzene, an important industrial chemical and component of gasoline, is a widely recognized cause of leukemia, but its association with non-Hodgkin lymphoma (NHL) is less clear. To clarify this issue, we undertook a systematic review of all case-control and cohort studies that identified probable occupational exposures to benzene and NHL morbidity or mortality. We identified 43 case-control studies of NHL outcomes that recognized persons with probable occupational exposure to benzene. Forty of these 43 (93%) studies show some elevation of NHL risk, with 23 of 43 (53%) studies finding statistically significant associations between NHL risk and probable benzene exposure. We also identified 26 studies of petroleum refinery workers reporting morbidity or mortality for lymphomas and all neoplasms and found that in 23 (88%), the rate of lymphoma morbidity or mortality was higher than that for all neoplasms. A substantial healthy-worker effect was evident in many of the studies and a comprehensive reevaluation of these studies with appropriate adjustments should be undertaken. Numerous studies have also reported associations between benzene exposure and the induction of lymphomas in mice. Further, because benzene is similar to alkylating drugs and radiation in producing leukemia, it is plausible that it might also produce lymphoma as they do and by similar mechanisms. Potential mechanisms include immunotoxicity and the induction of double-strand breaks with subsequent chromosome damage resulting in translocations and deletions. We conclude that, overall, the evidence supports an association between occupational benzene exposure and NHL. (Cancer Epidemiol Biomarkers Prev 2007;16(3):385–91)

Meta-analysis of benzene exposure and non-Hodgkin lymphoma: biases could mask an important association

Objectives: Benzene is a widely recognised cause of leukaemia but its association with non-Hodgkin’s lymphoma (NHL) is less well established. The goal of this project is to review the current published literature on this association. Methods: We performed a meta-analysis of cohort and case-control studies of benzene exposure and NHL and a meta-analysis of NHL and refinery work, a potential source of benzene exposure. Results: In 22 studies of benzene exposure, the summary relative risk for NHL was 1.22 (95 CI 1.02 to 1.47; one-sided p value  0.01). When studies that likely included unexposed subjects in the “exposed” group were excluded, the summary relative risk increased to 1.49 (95 CI 1.12 to 1.97, n  13), and when studies based solely on self-reported work history were excluded, the relative risk rose to 2.12 (95 CI 1.11 to 4.02, n  6). In refinery workers, the summary relative risk for NHL in all 21 studies was 1.21 (95 CI 1.00 to 1.46; p  0.02). When adjusted for the healthy worker effect, this relative risk estimate increased to 1.42 (95 CI 1.19 to 1.69). Conclusions: The finding of elevated relative risks in studies of both benzene exposure and refinery work provides further evidence that benzene exposure causes NHL. In addition, the finding of increased relative risks after removing studies that included unexposed or lesser exposed workers in “exposed” cohorts, and increased relative risk estimates after adjusting for the healthy worker effect, suggest that effects of benzene on NHL might be missed in occupational studies if these biases are not accounted for.

Relative contributions of four exposure pathways to influenza infection risk.

The relative contribution of four influenza virus exposure pathways-(1) virus-contaminated hand contact with facial membranes, (2) inhalation of respirable cough particles, (3) inhalation of inspirable cough particles, and (4) spray of cough droplets onto facial membranes-must be quantified to determine the potential efficacy of nonpharmaceutical interventions of transmission. We used a mathematical model to estimate the relative contributions of the four pathways to infection risk in the context of a person attending a bed-ridden family member ill with influenza. Considering the uncertainties in the sparse human subject influenza dose-response data, we assumed alternative ratios of 3,200:1 and 1:1 for the infectivity of inhaled respirable virus to intranasally instilled virus. For the 3,200:1 ratio, pathways (1), (2), and (4) contribute substantially to influenza risk: at a virus saliva concentration of 10(6) mL(-1), pathways (1), (2), (3), and (4) contribute, respectively, 31%, 17%, 0.52%, and 52% of the infection risk. With increasing virus concentrations, pathway (2) increases in importance, while pathway (4) decreases in importance. In contrast, for the 1:1 infectivity ratio, pathway (1) is the most important overall: at a virus saliva concentration of 10(6) mL(-1), pathways (1), (2), (3), and (4) contribute, respectively, 93%, 0.037%, 3.3%, and 3.7% of the infection risk. With increasing virus concentrations, pathway (3) increases in importance, while pathway (4) decreases in importance. Given the sparse knowledge concerning influenza dose and infectivity via different exposure pathways, nonpharmaceutical interventions for influenza should simultaneously address potential exposure via hand contact to the face, inhalation, and droplet spray.

Aerosol transmission of infectious disease.

Objective: The concept of aerosol transmission is developed to resolve limitations in conventional definitions of airborne and droplet transmission. Methods: The method was literature review. Results: An infectious aerosol is a collection of pathogen-laden particles in air. Aerosol particles may deposit onto or be inhaled by a susceptible person. Aerosol transmission is biologically plausible when infectious aerosols are generated by or from an infectious person, the pathogen remains viable in the environment for some period of time, and the target tissues in which the pathogen initiates infection are accessible to the aerosol. Biological plausibility of aerosol transmission is evaluated for Severe Acute Respiratory Syndrome coronavirus and norovirus and discussed for Mycobacterium tuberculosis, influenza, and Ebola virus. Conclusions: Aerosol transmission reflects a modern understanding of aerosol science and allows physically appropriate explanation and intervention selection for infectious diseases.

The Infectious Dose of Coxiella burnetii (Q Fever)

Quantitative estimation of an individuals risk of infection due to airborne pathogens requires knowledge of the pathogens infectious dose, in addition to estimates of the pathogens airborne concentration and the persons exposure duration. Based on our review of the published literature on Q fever, we conclude that the infectious dose of Coxiella burnetii is likely one rickettsia, and that the probability of a single organism initiating infection is approximately 0.9. Findings in experiments exposing guinea pigs to C. burnetii via intraperitoneal injection and inhalation of respirable aerosols firmly support a “one-hit” Poisson model of infection. Findings in experiments exposing human subjects to C. burnetii via inhalation of respirable aerosols fail to provide convincing evidence that the one-hit Poisson model applies to human infection; however, inference from the human studies is limited by the small numbers of subjects and lack of quantification of the exposure concentrations. Given the presence of C. burnetii in sputum, the prevalence of cough in Q fever patients, and the ability of the pathogen to initiate infection via the respiratory tract, we believe that person-to-person transmission of C. burnetii via inhalation of respiratory aerosol is possible.

The Infectious Dose of Francisella tularensis (Tularemia)

Quantitatively estimating an individuals risk of infection by an airborne pathogen requires knowledge of the expected dose and the pathogens infectious dose. Based on our review of the published literature on tularemia, we conclude that the infectious dose of Francisella tularensis varies among individuals, but that a substantial proportion of the population can be infected by a single bacillus. We also conclude that infection can be initiated by inhaling bacilli carried on respirable particles (diameters less than 10 µm) or nonrespirable particles (diameters between 10 µm and 100 µm). Regression analyses based on two-parameter Weibull and log-normal models of human inhalation dose-infection data aggregated across three studies indicate that approximately 30% of individuals who inhale a single F. tularensis bacillus will develop tularemia. Further, when the organism is carried on particles with diameters on the order of 1 µm, it is estimated that the deposition of a single bacillus produces infection in 40% to 50% of individuals; thus, when F. tularensis is carried on respirable particles, the estimated ID50 via inhalation is close to one deposited bacillus. These results are consistent with separate analyses using nonparametric methods and with experimental animal models in which infection is observed after injection of a single bacillus. The risk of person-to-person transmission of tularemia is generally considered negligible, perhaps due to a low concentration of F. tularensis in respiratory fluids. However, viable F. tularensis bacilli are present in human respiratory fluids, and can be carried in inspirable particles (diameters less than 100 µm) which are emitted during coughs and sneezes.

Critical Review and Uncertainty Analysis of Factors Influencing Influenza Transmission

Influenza remains a significant threat to public health, yet there is significant uncertainty about the routes of influenza transmission from an infectious source through the environment to a receptor, and their relative risks. Herein, data pertaining to factors that influence the environmental mediation of influenza transmission are critically reviewed, including: frequency, magnitude and size distribution and virus expiration, inactivation rates, environmental and self‐contact rates, and viral transfer efficiencies during contacts. Where appropriate, two‐stage Monte Carlo uncertainty analysis is used to characterize variability and uncertainty in the reported data. Significant uncertainties are present in most factors, due to: limitations in instrumentation or study realism; lack of documentation of data variability; or lack of study. These analyses, and future experimental work, will improve parameterization of influenza transmission and risk models, facilitating more robust characterization of the magnitude and uncertainty in infection risk.

The Infectious Dose of Variola (Smallpox) Virus

Quantitative estimation of an individuals risk of infection due to airborne pathogens requires knowledge of the pathogens infectious dose, in addition to estimates of the pathogens airborne concentration and the persons exposure duration. Based on our review of the published literature on poxvirus infection, we conclude that the infectious dose of variola (smallpox) virus is likely one virus particle and that infection can be initiated in either the upper respiratory tract or pulmonary region. Studies of airborne transmission of poxvirus in monkeys and rabbits show that primary infection can occur in both regions of the respiratory tract. A quantitative study of poxvirus inhalation transmission in rabbits indicates that the deposition of one pock-forming unit (PFU) carried on respirable particles can cause infection. Findings in both in vitro and in vivo studies of the number of virus particles comprising a PFU are consistent with a “one-hit” phenomenon—namely, the cellular uptake of just one virus particle can lead to infection of a cell or an area of cell growth, creating a pock (an infected area of cells). Variability in virulence among different virus strains may involve differences in the probability of infection per virus particle, where a highly virulent strain has a probability close to one of successful infection for each virus particle. In an analogous manner, variability in susceptibility to the same virus strain among different hosts may involve differences in the probability of infection per virus particle across different hosts.

Arsenic in drinking water and prostate cancer in Illinois counties: An ecologic study

BACKGROUND Inorganic arsenic is a lung, bladder, and skin carcinogen. One of the major sources of exposure to arsenic is through naturally contaminated drinking water. While positive associations have been observed between arsenic in drinking water and prostate cancer, few studies have explored this association in the United States. OBJECTIVES To evaluate the association between inorganic arsenic concentrations in community water systems and prostate cancer incidence in Illinois using an ecologic study design. METHODS Illinois Environmental Protection Agency data on arsenic concentrations in drinking water from community water systems throughout the state were linked with county-level prostate cancer incidence data from 2007 to 2011 from the Illinois State Cancer Registry. Incidence rates were indirectly standardized by age to calculate standardized incidence ratios (SIRs) for each county. A Poisson regression model was used to model the association between county-level SIRs and mean arsenic tertile (0.33-0.72, 0.73-1.60, and 1.61-16.23ppb), adjusting for potential confounders. RESULTS For counties with mean arsenic levels in the second tertile, the SIR was 1.05 (95% CI: 0.96-1.16). For counties with mean arsenic levels in the third tertile, the SIR was 1.10 (95% CI: 1.03-1.19). There was a significant linear dose-response relationship observed between mean arsenic levels and prostate cancer incidence (p for trend=0.003). CONCLUSIONS In this ecologic study, counties with higher mean arsenic levels in community water systems had significantly higher prostate cancer incidence. Individual-level studies of prostate cancer incidence and low-level arsenic exposure are needed.

Influenza infection risk and predominate exposure route: uncertainty analysis.

An effective nonpharmaceutical intervention for influenza interrupts an exposure route that contributes significantly to infection risk. Herein, we use uncertainty analysis (point-interval method) and Monte Carlo simulation to explore the magnitude of infection risk and predominant route of exposure. We utilized a previously published mathematical model of a susceptible person attending a bed-ridden infectious person. Infection risk is sensitive to the magnitude of virus emission and contact rates. The contribution of droplet spray exposure to infection risk increases with cough frequency, and decreases with virus concentration in cough particles. We consider two infectivity scenarios: greater infectivity of virus deposited in the upper respiratory tract than virus inhaled in respirable aerosols, based on human studies; and equal infectivity in the two locations, based on studies in guinea pigs. Given that virus have equal probability of infection throughout the respiratory tract, the mean overall infection risk is 9.8 × 10⁻² (95th percentile 0.78). However, when virus in the upper respiratory tract is less infectious than inhaled virus, the overall infection risk is several orders of magnitude lower. In this event, inhalation is a significant exposure route. Contact transmission is important in both infectivity scenarios. The presence of virus in only respirable particles increases the mean overall infection risk by 1-3 orders of magnitude, with inhalation contributing ≥ 99% of the infection risk. The analysis indicates that reduction of uncertainties in the concentration of virus in expiratory particles of different sizes, expiratory event frequency, and infectivity at different sites in the respiratory tract will clarify the predominate exposure routes for influenza.