Fundamental carcinogenic processes and their implications for low dose risk assessment.

Various possible models of carcinogenesis are analyzed with respect to low dose kinetics. The importance of background carcinogenesis upon the shape of the dose-response curve at low dose is emphasized. It is shown that, if carcinogenesis by an external agent acts additively with any already ongoing process, then under almost any model the response will be linear at low dose. Measures of the degree of linearity are obtained for multistage models of carcinogenesis, where it is shown that throughout the dose range where the extra risk is less than the spontaneous risk linear extrapolation must be quite accurate.

Late motor deficits of Chilean manganese miners: a blinded control study.

High-level chronic manganese (Mn) exposure produces dystonic rigidity and proximal tremor. The late effects of asymptomatic exposure are uncertain. To evaluate hand movements of asymptomatic Chilean miners, we utilized a manual tremormeter (EAP) and a digitizing tablet (MOVEMAP). In Andacollo, Chile, we examined 59 individuals aged > 50 years (mean age, 64.4 years). Twenty-seven exposed miners had heavy Mn dust exposure in Mn mines for more than 5 years (mean duration, 20.25 years), ending at least 5 years previously. Thirty-two control miners had never worked in Mn mines or had short-term Mn employment. Tests of resting tremor (EAP Tremormeter, MOVEMAP Steady paradigm), action tremor (MOVEMAP Square paradigm), and repetitive hand movements (EAP Tapping Test and Orthokinesimeter) differentiated performance of exposed miners from that of controls. Chronic asymptomatic Mn exposure results in detectable late-life abnormalities of movement.

Risk of benzene-induced leukemia predicted from the Pliofilm cohort.

This report updates the risk assessment by Crump and Allen for benzene-induced leukemia that was based on a cohort exposed to benzene in the manufacture of Pliofilm. The present study derives new risk estimates using data from follow-up through 1987 (whereas the earlier assessment only had follow-up available through 1978) and uses new exposure information for this cohort developed by Paustenbach et al. that accounts for a number of factors that were unknown or not fully evaluated in earlier exposure assessments. There was a significant excess of acute myelocytic or acute monocytic leukemia (AMML) (8-10 observed, 1.61 expected) in this cohort, and this end point also exhibited a strong dose-response trend. No other types of lymphatic or hematopoietic cancer were clearly linked to benzene exposure. Quantitative risk estimates were robust with respect to whether AMML or all leukemia was being modeled. They were also robust with respect whether the Paustenbach et al. or Crump and Allen exposure estimates were used (differences in risk estimates of no greater than 2-fold) as long as linear dose-response models were applied. However, whereas the Crump and Allen exposures predicted a linear dose response, the Paustenbach et al. exposures predicted a quadratic dose response. This departure from linearity was borderline significant (p = 0.08). Estimates of additional lifetime from 45 years of occupational exposure (lifetime exposure) to 1 ppm derived using he Paustenbach et al. exposure matrix and best-fitting (quadratic) models ranged from 0.020 to 0.036 per thousand, whereas corresponding estimates based on a linear dose response ranged from 1.6 to 3.1 per thousand.

Estimates of the proportion of chemicals that were carcinogenic or anticarcinogenic in bioassays conducted by the National Toxicology Program.

Estimates were made of the proportion of chemicals that were carcinogenic, anticarcinogenic, or either in 397 long-term bioassays conducted by the National Toxicology Program (NTP). The estimates were obtained from the global pattern of p-values obtained from statistical tests applied to individual experiments. These tests accounted for multiple comparisons using a randomization procedure and were found to operate at the correct level of significance. Representative estimates of the proportion of carcinogens [with 90% confidence intervals (CI)] compared to the NTP estimates were as follows: male mice, 0.32 (CI, 0.19-0.44), NTP = 0.29; female mice, 0. 28 (CI, 0.15-0.41), NTP = 0.34; male rats, 0.35 (CI, 0.23-0.47), NTP = 0.36; female rats, 0.34 (CI, 0.21-0.46), NTP = 0.28; all sexes and species, 0.59 (CI, 0.49-0.69), NTP = 0.51. Representative estimates of the proportion of anticarcinogens were as follows: male mice, 0. 34; female mice, 0.27; male rats, 0.40; female rats, 0.44; all sexes and species, 0.66. Thus, there was as much or more evidence in this study for anticarcinogenesis as carcinogenesis. Even though the estimators used were negatively biased, it was estimated that 85% of the chemicals were either carcinogenic or anticarcinogenic at some site in some sex-species group. This suggests that most chemicals given at high enough doses will cause some sort of perturbation in tumor rates.

Benchmark concentrations for methylmercury obtained from the Seychelles Child Development Study.

Methylmercury is a neurotoxin at high exposures, and the developing fetus is particularly susceptible. Because exposure to methylmercury is primarily through fish, concern has been expressed that the consumption of fish by pregnant women could adversely affect their fetuses. The reference dose for methylmercury established by the U.S. Environmental Protection Agency was based on a benchmark analysis of data from a poisoning episode in Iraq in which mothers consumed seed grain treated with methylmercury during pregnancy. However, exposures in this study were short term and at much higher levels than those that result from fish consumption. In contrast, the Agency for Toxic Substances and Disease Registry (ATSDR) based its proposed minimal risk level on a no-observed-adverse-effect level (NOAEL) derived from neurologic testing of children in the Seychelles Islands, where fish is an important dietary staple. Because no adverse effects from mercury were seen in the Seychelles study, the ATSDR considered the mean exposure in the study to be a NOAEL. However, a mean exposure may not be a good indicator of a no-effect exposure level. To provide an alternative basis for deriving an appropriate human exposure level from the Seychelles study, we conducted a benchmark analysis on these data. Our analysis included responses from batteries of neurologic tests applied to children at 6, 19, 29, and 66 months of age. We also analyzed developmental milestones (age first walked and first talked). We explored a number of dose-response models, sets of covariates to include in the models, and definitions of background response. Our analysis also involved modeling responses expressed as both continuous and quantal data. The most reliable analyses were considered to be represented by 144 calculated lower statistical bounds on the benchmark dose (BMDLs; the lower statistical bound on maternal mercury hair level corresponding to an increase of 0.1 in the probability of an adverse response) derived from the modeling of continuous responses. The average value of the BMDL in these 144 analyses was 25 ppm mercury in maternal hair, with a range of 19 to 30 ppm.

Estimates of the proportions of carcinogens and anticarcinogens in bioassays conducted by the U.S. National Toxicology Program. Application of a new meta-analytic approach.

A meta-analysis was performed in order to estimate the proportion of liver carcinogens, the proportion of chemicals carcinogenic at any site, and the corresponding proportion of anticarcinogens among chemicals tested in 397 long-term cancer bioassays conducted by the U.S. National Toxicology Program (NTP). Although the estimator used was negatively biased, the study provided persuasive evidence for a larger proportion of liver carcinogens (0.43, 90% CI: 0.35, 0.51) than was identified by the NTP (0.28). A larger proportion of chemicals carcinogenic at any site was also estimated (0.59, 90% CI: 0.49, 0.69) than was identified by the NTP (0.51), although this excess was not statistically significant. A larger proportion of anticarcinogens (0.66) was estimated than carcinogens (0.59). Despite the negative bias, it was estimated that 85% of the chemicals were either carcinogenic or anticarcinogenic at some site in some sex-species group. This suggests that most chemicals tested at high enough doses will cause some sort of perturbation in tumor rates.

Results from eleven years of neurological health surveillance at a manganese oxide and salt producing plant.

In 1983, Roels et al. (1987a, b) collected blood and urine samples and conducted neurological testing of workers at a manganese oxide and salt producing plant in Belgium, and at a nearby chemical plant. Workers from the manganese plant performed significantly worse than workers from the chemical plant on tests of short-term memory capacity, eye-hand coordination, hand steadiness, and visual reaction time. Between 1985 and 1996, workers at the manganese plant were tested routinely using the same battery of neurological tests and biological sampling that were employed by Roels et al. Blood and urine Mn levels remained comparable throughout the eleven years of testing to those measured in 1983 by Roels et al. On a gross basis, neurological test results during this period were comparable or superior to results obtained by Roels et al., despite the fact that workers were older and had been exposed longer. Large year-to-year differences were observed in some neurological test outcomes that could not be explained by age or Mn exposure. Older age was significantly associated with poorer performance on tests of short-term memory and eye-hand coordination. After controlling for age and year of testing, reduced hand steadiness was significantly associated with blood Mn and (Marginally) urine Mn, and both reaction time and one measure of hand steadiness were significantly associated with years of Mn exposure. No significant associations were found between any measure of Mn exposure and results from either short-term memory or eye-hand coordination tests. Investigations regarding whether neurological scores of individual workers studied by Roels et al. continued to worsen with continued occupational Mn exposure were hampered by lack of a suitable comparison group. However, there was no evidence that neurological effects seen earlier in these workers by Roels et al. were progressing towards clinical detectable signs.

Focused medical surveillance: a search for subclinical movement disorders in a cohort of U.S. workers exposed to low levels of manganese dust.

Seventy-five workers with recent and/or historical exposure to manganese (Mn) at a metal producing plant in northern Mississippi were closely matched with 75 control workers who had no known history of occupational exposure to Mn. Both plants are OSHA STAR work sites and share common medical, safety, and industrial hygiene services. Airborne Mn levels were assessed for each of twelve job categories at the Mn facility by collecting 63 side-by-side full-shift personal samples of both total and respirable Mn dust. Exposures of workers currently working with Mn averaged 0.066 mg/3 respirable and 0.18 mg/3 total Mn. An assessment of major equipment and work practice changes over the past several years and estimates of the resultant relative impacts on exposure was made. Based on this information and individual employment information, each worker's cumulative exposure to respirable and total Mn was estimated for the preceding 30 days, preceding year, and for the worker's entire employment history. Both Mn and control workers were administered multiple neuropsychological tests including tests of hand-eye coordination, hand steadiness, complex reaction time, and rapidity of finger tapping. A questionnaire was used to evaluate a worker's neuropsychological status. Performance decreased significantly with increasing age in tests of hand-eye coordination, complex reaction time and finger tapping speed. No effect of Mn exposure was found on the results of the questionnaire or any neuropsychological test.

Manganese exposures in Toronto during use of the gasoline additive, methylcyclopentadienyl manganese tricarbonyl.

A year-long population-weighted study of personal exposures to particulate matter (PM2.5) was conducted in Toronto while the manganese-containing additive, methylcyclopentadienyl manganese tricarbonyl (MMT), was present in gasoline at an average level of 11.9 mg Mn/l, which was higher than the maximum of 8.3 mg Mn/l allowed in the U.S. In this study, 925 three-day personal samples of PM2.5 (air concentration of aerosol with an aerodynamic diameter of less than 2.5 microm) were collected, along with a record of participants' occupations, personal habits, surroundings, and activities during sampling. Stationary samples of PM2.5 were collected indoors and outdoors at a subset of participants' homes over the same 3-day periods. Three-day samples of PM2.5 were also collected at fixed locations. Personal exposures to PM2.5 were highly influenced by exposure to tobacco smoke, and were poorly correlated with outdoor levels (Kendall's tau=0.13). The mean concentration of PM2.5 in homes (21 microg/m3) was significantly higher than the mean outdoor level (15 microg/m3). By contrast, the mean PM2.5 Mn concentration (air concentration of Mn in PM2.5) was higher outdoors (9.7 ng/m3) than indoors (5.5 ng/m3). Other than from tobacco smoke, there were no indications of significant indoor sources of PM2.5 Mn in homes. The most important predictor of exposure to PM2.5 was time spent in the subway, and a high level (428 ng/m3) of PM2.5 Mn was measured in the subway. The source of this Mn was hypothesized to be friction erosion of subway rails. Small, but statistically significant correlations were present between personal exposures to PM2.5 Mn and several traffic-related variables (time spent in transit, in a motor vehicle, near a roadway with traffic, and in a parking garage). However, in a stepwise regression that adjusted for weather and personal activities, time in a motor vehicle was the only traffic-related variable significantly associated with PM2.5 Mn, and it was only the 10th most important personal activity variable in the final model. Concentrations of PM2.5 Mn were higher at two fixed locations than outside of participants' homes, which were likely further from high traffic areas than the fixed sites. Likewise, outdoor and fixed site samples collected during periods that included weekend days contained lower air concentrations of Mn than samples collected during weekdays when traffic was heavier. On the other hand, the monthly average concentration of Mn in gasoline was negatively correlated with both outdoor and personal PM2.5 Mn, which suggests that traffic-related sources of Mn other than MMT may be present. After omitting participants with exposure to Mn from certain identifiable non-MMT sources (subway riders, metal workers and persons exposed to tobacco smoke), the average (median) personal exposure of the remaining 325 participants to PM2.5 Mn was reduced from 14 ng/m3 (8.5 ng/m3 ) to 8.3 ng/m3 (7.0 ng/m3). Potential sources of this residual Mn exposure include, in addition to MMT, naturally occurring Mn in the earth's crust, other occupational exposure, airborne release of Mn from industrial operations, and friction erosion of Mn from steel-containing products. Taken together, these facts (elimination of participants with Mn exposure from known non-MMT sources reduced average exposures by 40%, the existence of multiple non-MMT sources of the remaining Mn exposure, and the negative correlation between MMT usage and PM2.5 Mn) suggest that the preponderance of personal Mn exposure was from non-MMT sources.

Airborne asbestos levels in buildings: maintenance worker and occupant exposures.

A substantial number of air samples have been collected during the past few years to measure airborne asbestos levels in buildings with asbestos-containing materials (ACM). These samples fall into two categories: (i) samples collected to measure the exposure of workers while they were engaged in routine maintenance and repair activities; and (ii) samples collected during normal building activity to measure prevalent levels in buildings. The measurements derived from these samples have been compiled and summarized to provide estimates of the airborne asbestos exposure of workers engaged in routine maintenance and repair work and by other building occupants. These data indicate that maintenance and repair workers in buildings with ACM, after accounting for the frequency and duration of these types of activities, have annual exposure levels ranging from a median value of 0.002 fibers per cubic centimeter (f/cc) per year to 0.02 f/cc per year at the 90th percentile. Building occupants not involved in maintenance and repair work experience average exposure levels ranging from 0.00003 f/cc to 0.0005 f/cc.

An improved procedure for low-dose carcinogenic risk assessment from animal data.

An improved procedure is presented for estimating low-dose risks from dichotomous animal data based upon the multistage model of cancer. The procedure embodies both a proper fit to experimental data and an assumption of approximate linearity of the dose-response curve in the low-dose range. Because of this low-dose-linearity the procedure may be also considered to be a generalized method for linear extrapolation which uses all of the data. The extrapolation method is different from an earlier method based upon the multistage model in that an improved procedure is put forward for calculating statistical confidence limits and a recommendation is made for the integration of several data sets in the calculation of risk levels.

Does perchlorate in drinking water affect thyroid function in newborns or school-age children?

Perchlorate is known to suppress thyroid function by inhibiting uptake of iodide by the human thyroid at doses of 200 mg/day or greater. A study was conducted to investigate the potential effects of perchlorate in drinking water on thyroid function in newborns and school-age children. A total of 162 school-age children and 9784 newborns were studied in three proximate cities in northern Chile that have different concentrations of perchlorate in drinking water: Taltal (100 to 120 micrograms/L), Chañaral (5 to 7 micrograms/L), and Antofagasta (non-detectable: < 4 micrograms/L). Among schoolchildren, no difference was found in thyroid-stimulating hormone levels or goiter prevalence among lifelong residents of Taltal or Chañaral compared with those of Antofagasta, after adjusting for age, sex, and urinary iodine. No presumptive cases of congenital hypothyroidism were detected in Taltal or Chañaral; seven cases were detected in Antofagasta. Neonatal thyroid-stimulating hormone levels were significantly lower in Taltal compared with Antofagasta; this is opposite to the known pharmacological effect of perchlorate, and the magnitude of difference did not seem to be clinically significant. These findings do not support the hypothesis that perchlorate in drinking water at concentrations as high as 100 to 120 micrograms/L suppresses thyroid function in newborns or school-age children.

Evaluation of a population with occupational exposure to airborne ammonium perchlorate for possible acute or chronic effects on thyroid function.

Employees at an ammonium perchlorate production facility in Nevada and a larger control population from the same chemical complex without direct AP exposure were monitored extensively for airborne perchlorate exposure. Single-shift and working-lifetime cumulative dose estimates were made using standard breathing-rate estimates and assuming rapid absorption, based upon solubility. Calculated single-shift doses ranged from 0.2 to 436 micrograms/kg, with an average of 36 micrograms/kg. Working-lifetime cumulative doses in the higher exposure group ranged from 8,000 to 88,000 micrograms/kg, with an average of 38,000 micrograms/kg. Thyroid profiles, including free thyroxine index and thyroid-stimulating hormone level, were obtained both before shift and after shift to assess thyroid-axis perturbation due to single working-shift perchlorate exposure. Thyroid-function data were also analyzed with respect to estimates of cumulative exposure to assess any measurable chronic effects on thyroid gland function. Additionally, standard clinical blood test parameters of liver, kidney, and bone marrow function were evaluated to assess any measurable chronic effects of perchlorate exposure on those organs. Multiple regression was used to assess the effects of exposure variables and demographic variables on organ function parameters. No perchlorate-attributable effects on thyroid, bone marrow, kidney, or liver function were detected.

The linearized multistage model and the future of quantitative risk assessment.

The linearized multistage (LMS) model has for over 15 years been the default dose-response model used by the U.S. Environmental Protection Agency (USEPA) and other federal and state regulatory agencies in the United States for calculating quantitative estimates of low-dose carcinogenic risks from animal data. The LMS model is in essence a flexible statistical model that can describe both linear and non-linear dose-response patterns, and that produces an upper confidence bound on the linear low-dose slope of the dose-response curve. Unlike its namesake, the Armitage-Doll multistage model, the parameters of the LMS do not correspond to actual physiological phenomena. Thus the LMS is 'biological' only to the extent that the true biological dose response is linear at low dose and that low-dose slope is reflected in the experimental data. If the true dose response is non-linear the LMS upper bound may overestimate the true risk by many orders of magnitude. However, competing low-dose extrapolation models, including those derived from 'biologically-based models' that are capable of incorporating additional biological information, have not shown evidence to date of being able to produce quantitative estimates of low-dose risks that are any more accurate than those obtained from the LMS model. Further, even if these attempts were successful, the extent to which more accurate estimates of low-dose risks in a test animal species would translate into improved estimates of human risk is questionable. Thus, it does not appear possible at present to develop a quantitative approach that would be generally applicable and that would offer significant improvements upon the crude bounding estimates of the type provided by the LMS model. Draft USEPA guidelines for cancer risk assessment incorporate an approach similar to the LMS for carcinogens having a linear mode of action. However, under these guidelines quantitative estimates of low-dose risks would not be developed for carcinogens having a non-linear mode of action; instead dose-response modelling would be used in the experimental range to calculate an LED10* (a statistical lower bound on the dose corresponding to a 10% increase in risk), and safety factors would be applied to the LED10* to determine acceptable exposure levels for humans. This approach is very similar to the one presently used by USEPA for non-carcinogens. Rather than using one approach for carcinogens believed to have a linear mode of action and a different approach for all other health effects, it is suggested herein that it would be more appropriate to use an approach conceptually similar to the 'LED10*-safety factor' approach for all health effects, and not to routinely develop quantitative risk estimates from animal data.