Meta-analysis of stray voltage on dairy cattle.

A quantitative assessment of dairy cow responses to contact current (stray voltage) at 50 or 60 Hz was conducted using meta-analysis and pooled analysis methodology. The objective was to more accurately quantify the minimum exposure level (threshold) at which dairy cows respond and to identify sources of heterogeneity among studies. Several medical and agricultural databases were used to locate individual studies for the systematic literature review, from which 22 published studies of stray voltage and behavioral response or milk yield met our inclusion criteria. Meta-analysis models were constructed to assess the percentage of cows with a behavioral response at documented exposure levels, and the summary relative risk estimate for all exposure pathways combined was calculated for each 1-mA increment from 1.0 through 5.0 mA. The meta-analysis of percentage response showed that cows exhibited statistically significant first behavioral responses at 3.0 mA, response probability increased with exposure levels, and exposure pathways contributed to heterogeneity in the model. The pooled analysis of mean behavioral response threshold was based on experimental studies of ascending series of current exposures on 355 cows. The overall weighted mean for first behavioral response to current was 4.0 mA. Ten of the studies that met the inclusion criteria addressed milk production, but heterogeneity in exposure pathways, patterns, and duration precluded meta-analysis or data pooling. The milk production studies ranged in size from 4 to 48 cows and used switchback or paired design to increase power. A qualitative narrative review of these studies indicated that production was not affected by exposure to contact current at levels of 3 mA or lower for exposures of up to 21 d or 4 wk.

Mobile phones, mobile phone base stations and cancer: a review.

There have been reports in the media and claims in the courts that radiofrequency (RF) emissions from mobile phones are a cause of cancer, and there have been numerous public objections to the siting of mobile phone base antennas because of a fear of cancer. This review summarizes the current state of evidence concerning whether the RF energy used for wireless communication might be carcinogenic. Relevant studies were identified by searching MedLine with a combination of exposure and endpoint terms. This was supplemented by a review of the over 1700 citations assembled by the Institute of Electrical and Electronics Engineers (IEEE) International Committee on Electromagnetic Safety as part of their updating of the IEEE C95.1 RF energy safety guidelines. Where there were multiple studies, preference was given to recent reports, to positive reports of effects and to attempts to confirm such positive reports. Biophysical considerations indicate that there is little theoretical basis for anticipating that RF energy would have significant biological effects at the power levels used by modern mobile phones and their base station antennas. The epidemiological evidence for a causal association between cancer and RF energy is weak and limited. Animal studies have provided no consistent evidence that exposure to RF energy at non-thermal intensities causes or promotes cancer. Extensive in vitro studies have found no consistent evidence of genotoxic potential, but in vitro studies assessing the epigenetic potential of RF energy are limited. Overall, a weight-of-evidence evaluation shows that the current evidence for a causal association between cancer and exposure to RF energy is weak and unconvincing. However, the existing epidemiology is limited and the possibility of epigenetic effects has not been thoroughly evaluated, so that additional research in those areas will be required for a more thorough assessment of the possibility of a causal connection between cancer and the RF energy from mobile telecommunications.

Using human data to protect the public's health.

The value of using human data in the assessment and management of risk is evaluated. Although the use of such data has a long and successful history with environmental contaminants and the development of drugs and commercial chemicals, recent deliberations within the Environmental Protection Agency (EPA) have questioned this practice in part. Specifically, we evaluate the degree to which reference doses (RfDs) and reference concentrations (RfCs) derived from human data on EPA's Integrated Risk Information System (IRIS) differ with RfDs and RfCs that we estimate from experimental animal data. We also use several minimal risk levels of the Agency for Toxic Substances and Disease Registry (ATSDR) and tolerable intakes of Health Canada in this comparison. Human-based RfDs are more than threefold lower than the corresponding animal-based RfDs for 23% of the comparisons. Human- based RfDs or RfCs are lower than corresponding animal-based RfDs or RfCs for 36% of the comparisons. Furthermore, for 10 of 43 possible comparisons, insufficient experimental animal data are readily available or data are inappropriate to estimate either RfDs or RfCs. We also discuss human pharmacokinetic data from volunteer studies and mechanistic studies with human tissues in vitro and demonstrate through a series of case discussions that utilization of such data is important when making decisions to protect exposed individuals. Moreover, physiologically based pharmacokinetic (PBPK) modeling evaluates critical information in assessing interindividual variability and identifying at-risk populations. Within the limits of our analysis, we conclude that the direct use and interpretation of human data, in conjunction with data gathered from experimental animals, are public health protective policies that should be encouraged.

Radio frequency radiation exposure standards: considerations for harmonization.

Radio frequency radiation exposure standards vary in origin, development process, legal status, and in the actual exposure limits. To identify the sources of differences in limits, we evaluated technical aspects of eight standards that included supporting information on the scientific data and rationale. Comparisons were made among the standards by examining the scope of the underlying database, the rationales for safety factors and other issues underlying exposure limits in the energy-deposition range (0.1 MHz to 10.0 GHz) and in the surface-heating range (about 10 or 15 GHz to 300 GHz). The framework for this assessment was based on the methods recommended by the scientific and regulatory organizations for developing health-based exposure limits. General guidelines for performing risk assessments for threshold acting agents have been developed by the U.S. Environmental Protection Agency, Health Canada's Environmental Health Directorate, and the International Program on Chemical Safety of the World Health Organization. This general methodology was applied to radiofrequency radiation for this assessment. Because these methods strive to identify scientific issues and separate them from risk management or policy, they provide a basis for evaluation of standards in this paper. This distinction can provide a foundation for the longer-term goal of global harmonization of radio frequency radiation standards. Each of the standards evaluated in the energy-deposition range was found to use the same basic restriction, based on biological data and a 10-fold safety factor, yet explanations reflect different interpretations of the underlying biological data. Rationales differ for the magnitude of the safety factor, for the circumstances of exposure, for the nature of sensitive populations, and for the presumed health status of the individuals for whom the basic restriction is applicable. In the surface-heating range, broad variability in exposure limits are seen in the limit itself, as well as in the approach to time averaging and frequency dependence. Averaging times differ among standards, as do tissue geometries for defining partial-body exposures. The differences in approaches to develop the standards do not completely explain differences among the exposure limits, and methods for computing exposure limits from basic restrictions are not always defined. This analysis suggests harmonization of standards will require more detailed review and coordination of biological and engineering data and of policy options.

Hazard identification and dose response of ingested nickel-soluble salts.

People can ingest soluble nickel compounds as a normal constituent of food or as a contaminant in drinking water. This paper presents an assessment of the noncancer and cancer human health risks from ingestion of soluble nickel compounds. A reference dose (RfD) of 8 x 10(-3) mg Ni/kg/day in addition to the amount in food was calculated, based on albuminuria in female rats exposed to nickel sulfate in drinking water for 6 months (A. Vyskocil et al., 1994, Hum. Exp. Toxicol. 13, 689-693). This RfD is comparable to the current RfD based on decreased body weight in a chronic feeding study in rats (A. M. Ambrose et al., 1976, J. Food Sci. Technol. 13, 181-187). The potential for nickel-induced reproductive toxicity was also taken into account in the derivation of the RfD. There are a number of negative animal bioassays with soluble nickel salts, but all of them have deficiencies that preclude a definitive conclusion. According to EPA's 1996 draft cancer guidelines, the carcinogenic potential of oral exposure to soluble nickel "cannot be determined because there are inadequate data to perform an assessment."

Cell phones and cancer: what is the evidence for a connection?

There have been allegations in the media and in the courts that cell phones and other types of hand-held transceivers are a cause of cancer. There have also been numerous public objections to the siting of TV, radio and cell phone transmission facilities because of a fear of cancer induction. A recent publication in Radiation Research by Repacholi et al. (147, 631-640, 1997) which suggests that exposure to radiofrequency (RF) radiation may increase lymphoma incidence in mice has contributed to this controversy. The goal of this review is to provide biomedical researchers a brief overview of the existing RF radiation-cancer studies. This article begins with a brief review of the physics and technology of cell phones. It then reviews the existing epidemiological studies of RF radiation, identifying gaps in our knowledge. Finally, the review discusses the cytogenetics literature on RF radiation and the whole-animal RF-radiation carcinogenesis studies. The epidemiological evidence for an association between RF radiation and cancer is found to be weak and inconsistent, the laboratory studies generally do not suggest that cell phone RF radiation has genotoxic or epigenetic activity, and a cell phone RF radiation-cancer connection is found to be physically implausible. Overall, the existing evidence for a causal relationship between RF radiation from cell phones and cancer is found to be weak to nonexistent.

Thermal models for microwave hazards and their role in standards development.

We consider the thermal response of the body to radiofrequency (RF) energy, with emphasis on partial-body exposure, to assess potential thermal hazards. The thermal analysis is based on Pennes' bioheat equation. In this model, the thermal response is governed by two time constants. One (tau1) pertains to heat convection by blood flow and is (for physiologically normal perfusion rates) on the order of 3 min. The second (tau2) characterizes heat conduction, and varies as the square of a distance that characterizes the spatial extent of the heating. We examine three idealized cases. The first is a region of tissue with an insulated surface, subject to irradiation with an exponentially decreasing SAR, which models a large surface area of tissue exposed to microwaves. The second is a region of tissue in contact with a hemispherical electrode that passes current into it, which models exposure from contact with a conductor. The third is a region of tissue with an insulated surface, subject to heating from a dipole located close to it. In all three cases, we estimate the maximum steady-state temperature increase as a function of the relevant electrical and thermal parameters and the thresholds for thermal hazard. We conclude that thermal models are a potentially fruitful but underutilized means of analyzing thermal hazards from RF fields. A quantitative analysis of such hazards enables the development of data-based uncertainty factors, which can replace arbitrary "safety factors" in developing exposure limits. Finally, we comment on the need to marry quantitative modeling of data and risk assessment, and to incorporate contemporary approaches to risk assessment into RF standards development.

Statistical uncertainty in the no-observed-adverse-effect level.

The no-observed-adverse-effect level (NOAEL) is a dose value that U.S. EPA reduces by uncertainty factors (UF) and modifying factors (MF) to obtain a reference dose (RfD) for input to regulatory decision making. Whether the true added risk at the NOAEL is below an acceptable level, however, is a source of statistical uncertainty itself. As several authors have previously noted, the probability that added risk at the NOAEL is not negligibly small increases as sample sizes decrease. This is because the definition of the NOAEL statistically controls for the chance of a false-positive error, but not for a false-negative error. The false-positive rate is the test level set by the user in testing for a statistically significant dose effect, typically 0.05. When it is held fixed, the increase in statistical uncertainty as sample size decreases produces an increase in the false-negative rate. Hence, the fewer data available for statistical inference, the higher the expected value of the NOAEL and the less toxic an agent is likely to appear. The solution lies in calculating the probability that a statistical procedure used will detect the maximum added risk acceptable for health regulation (the "power" at that added risk). If the observed response in a dose group is not significantly elevated relative to the control group, and the power for detecting a difference is low as well, then the statistical evidence is inconclusive. In such a case, additional data or other sources of information are needed for evaluating added risk. These concepts are illustrated for examples from the literature with dichotomous (quantal response) data and categorical (severity) data, using a new statistical procedure.

Thyroid follicular cell carcinogenesis.

Ample information in experimental animals indicates a relationship between inhibition of thyroid-pituitary homeostasis and the developmental thyroid follicular cell neoplasms. This is generally the case when there are long-term reductions in circulating thyroid hormones which have triggered increases in circulating thyroid stimulating hormone. Such hormonal derangements leading to neoplasms have been produced by different regimens, including dietary iodide deficiency, subtotal thyroidectomy, and administration of natural and xenobiotic chemical substances. The carcinogenic process proceeds through a number of stages, including follicular cell hypertrophy, hyperplasia, and benign and sometimes malignant neoplasms. Given the interrelationship between the thyroid and pituitary glands, conditions that result in stimulation of the thyroid can also result in stimulation of the pituitary, with the development of hyperplastic and neoplastic changes. The progression of events leading to thyroid (and pituitary) neoplasms can be reversed under certain circumstances be reestablishing thyroid-pituitary homeostasis. Most chemicals that have induced follicular cell tumors seem to operate through inhibition of the synthesis of thyroid hormone or an increase in their degradation and removal. For some of these compounds, it appears that genotoxic reactions may not be playing a dominant role in the carcinogenic process. A seemingly small group of thyroid carcinogens seems to lack influence on thyroid-pituitary status and may in part be operating via their genotoxic potential. In contrast with the well-established relationship between thyroid-pituitary derangement and follicular cell neoplasms in animals, the state of information in humans is much less certain. At this time, ionizing radiation is the only acknowledged human thyroid carcinogen, a finding well established in experimental systems as well. Although humans respond to goitrogenic stimuli as do animals, with the development of cellular hypertrophy, hyperplasia, and under certain circumstances nodular lesions, disagreement exists as to whether malignant transformation occurs in any predictable manner. It would seem that if humans develop thyroid tumors following long-term derangement in thyroid-pituitary status, they may be less sensitive than the commonly used animal models.

Human variability in susceptibility to toxic chemicals--a preliminary analysis of pharmacokinetic data from normal volunteers.

The tenfold "uncertainty" factor traditionally used to guard against human interindividual differences in susceptibility to toxicity is not based on human observations. To begin to build a basis for quantifying an important component of overall variability in susceptibility to toxicity, a data base has been constructed of individual measurements of key pharmacokinetic parameters for specific substances (mostly drugs) in groups of at least five healthy adults. 72 of the 101 data sets studied were positively skewed, indicating that the distributions are generally closer to expectations for log-normal distributions than for normal distributions. Measurements of interindividual variability in elimination half-lives, maximal blood concentrations, and AUC (area under the curve of blood concentration by time) have median values of log10 geometric standard deviations in the range of 0.11-0.145. For the median chemical, therefore, a tenfold difference in these pharmacokinetic parameters would correspond to 7-9 standard deviations in populations of normal healthy adults. For one relatively lipophilic chemical, however, interindividual variability in maximal blood concentration and AUC was 0.4--implying that a tenfold difference would correspond to only about 2.5 standard deviations for those parameters in the human population. The parameters studied to date are only components of overall susceptibility to toxic agents, and do not include contributions from variability in exposure- and response-determining parameters. The current study also implicitly excludes most human interindividual variability from age and illness. When these other sources of variability are included in an overall analysis of variability in susceptibility, it is likely that a tenfold difference will correspond to fewer standard deviations in the overall population, and correspondingly greater numbers of people at risk of toxicity.

Improving the use of epidemiologic data in health risk assessment.

Epidemiologic data with quantitative exposure measures is infrequently available for specific environmental agents. This lack of exposure measures creates confusion in interpreting epidemiologic data and therefore has impeded its efficient use in health risk analysis. This paper discusses screening and evaluating epidemiologic studies for use in assessing health risk. It also describes the larger role of epidemiology in reducing uncertainties in risk analysis. The approach recognizes that the various designs used to increase statistical power and to control for covariables have different functions in contemporary risk assessment as practiced by regulatory agencies. Each of these study designs is categorized for its role in risk analysis as useful for hazard identification or for dose-response assessment. Studies presenting geographic correlations are construed to be not directly useful in health risk assessment. The numerical level of the exposure data is a deciding factor in using valid epidemiologic studies. However, data measured on an ordinal scale can be used in qualitative assessments and can demonstrate the strength of the relationship. The application of this procedure is illustrated using epidemiologic studies on the carcinogenicity of chemicals contaminated with dioxins.

Comparing epidemiologic studies of ingested asbestos for use in risk assessment.

Epidemiologic data can be used in risk assessment in various ways: to calculate the dose-response relationship between exposure levels and adverse effects; to establish ranges of exposure known to be safe or unsafe; to verify an endpoint in humans derived from a route or species extrapolation; to support assumptions necessary for performing extrapolation procedures. These points are illustrated in the risk assessment for exposure to asbestos in drinking water. A previous risk assessment for asbestos, the EPA's Ambient Water Quality Criteria (AWQC) for Asbestos, was derived from cohort studies of inhalation exposure. Epidemiologic studies of ingested asbestos, all of geographical correlation design, were compared on the basis of their ability to add information in support of both the route extrapolation and low-dose extrapolation used in this risk assessment. Results of these ingestion studies were inconsistent due to variable ability to detect a risk from chronic low-level exposure. After preliminary comparisons of factors that determine scientific validity and statistical power, two ingestion studies were selected to determine if they had the potential to detect the risk predicted by the AWQC. This evaluation has shown that these studies do not offer quantitative data for estimating levels associated with a defined risk. Due to short exposure duration and limited power, clearly safe and clearly unsafe ranges could not be definitely identified. The most appropriate ingestion studies suggest, but do not prove, the endpoint derived from the route extrapolation in the AWQC.

Absence of a relationship between smoking and diabetic microangiopathy.

The relationship between cigarette smoking and retinopathy and proteinuria was examined in a group of 973 subjects with diabetes. Other variables known to influence the risk of microangiopathy were also measured in a standardized fashion (e.g., duration of diabetes, blood glucose, blood pressure). The characteristics of smokers and nonsmokers were studied in detail. It was therefore possible to take into account the effects of confounding variables on the relationship between smoking and risk of microangiopathy. Associations between smoking and risk of microangiopathies, previously reported in some of the smaller studies, were not confirmed in this larger study.

Morphologic types of breast cancer: age, bilaterality, and family history.

Morphologic type is not generally included in the study of cancer risk factors. In breast cancer, attention is being given to age at diagnosis. In this study cases were analyzed by morphologic type as well as age at diagnosis for occurrence of bilateral disease and for family history of breast cancer. Of the morphologic types which were more frequent in younger patients--lobular in situ, medullary, and intraductal comedo--only lobular in situ had an increased frequency of bilaterality (fourfold increase). Of these, only patients with intraductal comedo reported familial breast cancer more frequently than the average. Lobular infiltrating carcinoma is diagnosed more frequently in elderly patients and is associated with 2.6 times more bilaterality and increased familial risk. Diagnosis at age 45 to 54 is also associated with increased bilaterality, but the diagnosis of lobular carcinoma has much stronger association with bilaterality than early age at diagnosis. Because of the high risk of bilaterality in lobular neoplasia and in those with a family history of cancer occurring before the menopause, bilateral biopsies and subsequent screening for malignancy should be done in these women.