Trichloroethylene and cancer in humans: recognizing the need for an evidence based analysis.
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Carcinogens↗
Biomedical subjects
Robert C James
Publications and source records attributed to Robert C James.
Evidence-based toxicology: a comprehensive framework for causation.
This paper identifies deficiencies in some current practices of causation and risk evaluation by toxicologists and formulates an evidence-based solution. The practice of toxicology focuses on adverse health events caused by physical or chemical agents. Some relations between agents and events are identified risks, meaning unwanted events known to occur at some frequency. However, other relations that are only possibilities--not known to occur (and may never be realized)--also are sometimes called risks and are even expressed quantitatively. The seemingly slight differences in connotation among various uses of the word 'risk' conceal deeply philosophic differences in the epistemology of harm. We label as 'nomological possibilities' (not as risks) all predictions of harm that are known not to be physically or logically impossible. Some of these nomological possibilities are known to be causal. We term them 'epistemic'. Epistemic possibilities are risks. The remaining nomological possibilities are called 'uncertainties'. Distinguishing risks (epistemic relationships) from among all nomological possibilities requires knowledge of causation. Causality becomes knowable when scientific experiments demonstrate, in a strong, consistent (repeatable), specific, dose-dependent, coherent, temporal and predictive manner that a change in a stimulus determines an asymmetric, directional change in the effect. Many believe that a similar set of characteristics, popularly called the 'Hill Criteria', make it possible, if knowledge is robust, to infer causation from only observational (nonexperimental) studies, where allocation of test subjects or items is not under the control of the investigator. Until the 1980s, medical decisions about diagnosis, prevention, treatment or harm were often made authoritatively. Rather than employing a rigorous evaluation of causal relationships and applying these criteria to the published knowledge, the field of medicine was dominated by authority-based opinions, expressed by experts (or consensus groups of experts) relying on their education, training, experience, wisdom, prestige, intuition, skill and improvisation. In response, evidence-based medicine (EBM) was developed, to make a conscientious, explicit and judicious use of current best evidence in deciding about the care of individual patients. Now globally embraced, EBM employs a structured, 'transparent' protocol for carrying out a deliberate, objective, unbiased and systematic review of the evidence about a formally framed question. Not only in medicine, but now in dentistry, engineering and other fields that have adapted the methods of EBM, it is the quality of the evidence and the rigor of the analysis through evidence-based logic (EBL), rather than the professional standing of the reviewer, that leads to evidence-based conclusions about what is known. Recent studies have disclosed that toxicologists (individually or in expert groups), not unlike their medical counterparts prior to EBM, show distressing variations in their biases with regard to data selection, data interpretation and data evaluation when performing reviews for causation analyses. Moreover, toxicologists often fail to acknowledge explicitly (particularly in regulatory and policy-making arenas) when shortcomings in the evidence necessitate reliance upon authority-based opinions, rather than evidence-based conclusions (Guzelian PS, Guzelian CP. Authority-based explanation. Science 2004; 303: 1468-69). Accordingly, for answering questions about general and specific causation, we have constructed a framework for evidence-based toxicology (EBT), derived from the accepted principles of EBM and expressed succinctly as three stages, comprising 12 total steps. These are: 1) collecting and evaluating the relevant data (Source, Exposure, Dose, Diagnosis); 2) collecting and evaluating the relevant knowledge (Frame the question, Assemble the relevant (delimited) literature, Assess and critique the literature); and 3) Joining data with knowledge to arrive at a conclusion (General causation--answer to the framed question, Dose-response, Timing, Alternative cause, Coherence). The second of these stages (which amounts to an analysis of general causation), is addressed by an EBM-styled approach (adapted for the infrequent availability of human experimental studies in environmental toxicology). This involves assembling literature (through documented algorithms for database queries), excluding irrelevancies by use of delimiters as filters, and ranking and rating the remaining articles for strength of study design and for quality of execution gauged by application of either a ready-made quality assessment instrument or a custom designed checklist or scale. The results of this systematic review (including a structured review of relevant animal and in vitro studies) are then themselves systematically used to determine which causation criteria are fulfilled. Toxicology is maturing from a derivative science largely devoted to routinized performance and interpretation of safety tests, to a discipline deeply enmeshed in the remarkable advances in biochemistry and molecular biology to better understanding the nature and mechanism of adverse effects caused by chemicals. It is time for toxicologists, like scientists in other fields, to formalize a method for differentiating settled toxicological knowledge of risk from mere nomological possibility, and for communicating their conclusions to other scientists and the public. It is time for EBT.
Animals↗
Development of an oral cancer slope factor for Aroclor 1268.
Rodent cancer bioassays indicate that substantial differences exist among PCB mixtures in terms of tumorigenic response, although no bioassay has been conducted with Aroclor 1268. The USEPA has used data from these studies to develop three sets of PCB cancer slope factors (CSFs) ranging from 0.07 to 2.0(mg/kg-day)(-1). Selection of the appropriate CSF for risk assessment purposes is largely a function of the exposure circumstances rather than the PCB mixture involved. Since the congener composition of Aroclor 1268 differs substantially from that of the predominant PCB mixture (Aroclor 1254) used to derive the CSFs, the validity of applying existing CSFs to Aroclor 1268 is questionable. We have therefore undertaken the task of developing cancer potency estimates specifically for Aroclor 1268. Potency estimation approaches for Aroclor 1268 were based in part on existing potency estimates for other PCB mixtures, coupled with the relative 2,3,7,8-tetrachlorodibenzo-p-dioxin toxic equivalents (TEQ) content and bioaccumulation potential of PCB mixtures. As such, both Ah-dependent and independent mechanisms of tumorigenesis were considered relevant. Both empirical evidence and mechanistic considerations indicate Aroclor 1268 is substantially less toxic and carcinogenic than the PCB mixtures that have been used by the USEPA to develop CSFs. The present analysis indicates that Aroclor 1268 is likely to be 1-2 orders of magnitude less potent than Aroclor 1254 in terms of potential tumorigenicity. Therefore, we suggest an upper-bound cancer potency factor of 0.27(mg/kg-day)(-1) for Aroclor 1268, a value that is 7- to 8-fold lower than the USEPA's current default, but nonetheless adequately conservative.
Animals↗
Geographic location of commercial plasma donation clinics in the United States, 1980-1995.
OBJECTIVE: We examined the location of commercial plasma donation centers in the United States over the period 1980 to 1995 relative to the geographic distribution of risk behaviors associated with transfusion-transmissible infections. METHODS: The census tract locations of commercial source plasma clinics were described by measures of neighborhood social disadvantage and the prevalence of illicit drug use and active local drug economies. RESULTS: Depending on the measure of social environment used, commercial plasma clinics were 5 to 8 times more likely to be located in census tracts designated high-risk than would be expected by chance. CONCLUSIONS: Commercial source plasma clinics were overrepresented in neighborhoods with very active local drug economies. These patterns persisted after the links between human immunodeficiency virus and hepatitis C virus infections and plasma products had been established and may present risks to blood system safety.
Ambulatory Care Facilities↗
A model for non-communicable disease surveillance in Canada: the prairie pilot diabetes surveillance system.
The Prairie Pilot Diabetes Surveillance Project was organized to design and test a prototype population-based surveillance system, using administrative data, for a chronic disease exemplar - diabetes mellitus. The Canadian model of a public health surveillance system for chronic conditions described here specifies a process by which administrative and claims data arising from provincial health insurance programs are merged into an annual person-level summary file (APLSF), yielding one summary record for each person insured within each province. The APLSF is the basis for a variety of estimates, including incidence, prevalence, mortality, complication rates and health services utilization. The model was used to produce comparable interprovincial estimates of several parameters with respect to diabetes for the entire population in the provinces of Alberta, Manitoba and Saskatchewan. All processing of identifiable health data occurred within the provinces where the data were generated. Combining results across provinces was based on further aggregation of the summary data from each province and not by pooling of identifiable person-level data. On the basis of preliminary outputs for diabetes mellitus, the model appears to provide coherent estimates of key diabetes parameters and reflects anticipated differences in health services and outcomes, by disease state. Three characteristics of the model recommend it as a resource for non-communicable disease surveillance in Canada: a) it maximizes the utility of existing data; b) it includes both those with and those without the disease in question; and c) it respects provincial legislation regarding personal health data, yet permits reporting of multi-provincial, population-based data.
Adolescent↗
Incident cerebrovascular disease in rural and urban Alberta.
STUDY OBJECTIVE: This study examines the pattern of incidence and health service utilisation of cerebrovascular disease cases in urban and rural areas within a publicly funded health care system. DESIGN: A population-based study covering a large geographic region, using population-wide administrative health data. Age- and sex-standardised incidence and mortality rates were calculated for rural and urban areas. Final status (discharge or death), place of service and place of residence were reported for all cases across several different subsets of cerebrovascular disease. SETTING: The province of Alberta, located in western Canada. PARTICIPANTS: Incident cases of cerebrovascular disease (stroke and transient ischaemic attack) and 4 different definitions of incident stroke were identified from data on emergency department admissions in the 1999/2000 fiscal year. MAIN RESULTS: The rate of cerebrovascular disease per 10,000 was similar between urban (13.24) and rural (13.82) areas. Rural residents frequently reported their incident episode to urban emergency departments. Although the mortality is similar between urban and rural residents, rural dwellers die more frequently in the emergency department setting than urban dwellers, who die more often as in-patients. CONCLUSIONS: Overall mortality is similar between urban and rural residents. A large proportion of rural residents receive diagnoses and treatment for cerebrovascular disease in urban areas. Location of service and location of death differs between rural and urban cases of cerebrovascular disease.
Adolescent↗
Regional comparisons of inpatient and outpatient patterns of cerebrovascular disease diagnosis in the province of Alberta.
The diagnosis of cerebrovascular disease (CBVD) from administrative data has been critically examined by epidemiologists in recent years. Much of the existing literature suggests that hospital discharge diagnoses based on ICD-9-CM codes are an unreliable source of information for determining a diagnosis of stroke, particularly when four- and five-digit codes are used. We examined how diagnoses for CBVD in hospital inpatient and outpatient facilities vary between rural and urban areas and among the 16 administrative health regions. Our analysis revealed differences in diagnostic patterns between the two sources of data, differences between rural and urban areas, and variation across most of the regions. Geographic variation in health service utilization, diagnostic practices, specialty of the physician making the diagnosis, and disease burden may explain our findings. Our results suggest that the diagnosis of patients attending rural facilities are either coded differently (and less precisely) than those of urban residents or are coded more precisely only after the patients attend urban facilities. Regional differences in coding practices show that any CBVD surveillance system based on administrative data requires a large-scale (in this case, province-wide) and person-oriented approach.
Alberta↗
Evaluation of the carcinogenicity of 1,1-dichloroethylene (vinylidene chloride).
The U.S. Environmental Protection Agency has classified 1,1-dichloroethylene (vinylidene chloride; VDC) as a "C" carcinogen and has developed an inhalation unit risk value and an oral cancer slope factor for this chemical. The development and use of these cancer potency estimates for risk assessment purposes are questionable. The inhalation unit risk value is based on increased kidney adenocarcinomas in Swiss mice from one study. This type of cancer was not increased in female mice or in rats or hamsters in the same study nor in male mice of a similar strain in another study with higher VDC exposures. The VDC oral cancer slope factor is based on a non-statistically significant increase in adrenal pheochromocytomas in male rats following oral exposure in a standard National Toxicology Program chronic bioassay. Both human and animal literature relevant to VDC carcinogenicity was reviewed according to the USEPA draft Guidelines for Carcinogen Risk Assessment with the objective of determining the weight-of-evidence for VDC carcinogenicity. We conclude that information currently available for VDC is most appropriately characterized in a weight-of-evidence narrative by the descriptor "inadequate for an assessment of human carcinogenic potential." For chemicals with this descriptor, dose-response assessment is not indicated. Under this guidance, quantitative estimates of cancer risks associated with VDC exposure are inappropriate until additional, more definitive evidence for human carcinogenicity becomes available.
Administration, Inhalation↗