The REACH registration process: A case study of metallic aluminium, aluminium oxide and aluminium hydroxide.

The European Union's REACH Regulation requires determination of potential health and environmental effects of chemicals in commerce. The present case study examines the application of REACH guidance for health hazard assessments of three high production volume (HPV) aluminium (Al) substances: metallic aluminium, aluminium oxide, and aluminium hydroxide. Among the potential adverse health consequences of aluminium exposure, neurotoxicity is one of the most sensitive targets of Al toxicity and the most critical endpoint. This case study illustrates integration of data from multiple lines of evidence into REACH weight of evidence evaluations. This case study then explains how those results support regulatory decisions on classification and labelling. Challenges in the REACH appraisal of Al compounds include speciation, solubility and bioavailability, application of assessment factors, read-across rationale and differences with existing regulatory standards. Lessons learned from the present case study relate to identification and evaluation of toxicologic and epidemiologic data; assessing data relevance and reliability; development of derived no-effect levels (DNELs); addressing data gaps and preparation of chemical safety reports.

Database of radiogenic cancer in experimental animals exposed to low doses of ionizing radiation.

For decades, there have been debates regarding the nature of the relationship between exposure to low doses of ionizing radiation and cancer risk. Under the linear no-threshold hypothesis, which serves as a theoretical basis for current radiation protection standards, the risk of cancer at low levels of exposure is presumed to be directly proportional to dose. Opponents of this hypothesis claim that there are threshold doses for radiation carcinogenesis, or even a reduction in cancer risk at low doses (a phenomenon referred to as "radiation hormesis"). Epidemiological, animal, molecular, and cellular studies were conducted to resolve this controversy, although each of these study types has its strengths and limitations. Although the results of animal experiments are not directly applicable to humans, data can substantially add to our knowledge on the form of relationship between radiation dose and cancer risk in a wide range of doses. Laboratory animals are a homogeneous population with little biological variability; animal experiments are conducted under controlled conditions with good estimates of radiation doses. In order to address the question of whether or not the dose-response curve for radiation carcinogens is linear at low doses, a comprehensive database of animal carcinogenesis experiments was assembled involving exposure to different types of ionizing gradation. The database includes virtually all publicly accessible data on the induction of radiogenic cancer in laboratory mammals. This review provides a descriptive overview of the experiments included in the database, along with a qualitative assessment of the shape of the dose-response relationship for radiation carcinogenesis at low doses in experimental animals.

A meta-analysis of evidence for hormesis in animal radiation carcinogenesis, including a discussion of potential pitfalls in statistical analyses to detect hormesis.

A database containing 800 datasets on the incidence of specific tumor types from 262 radiation carcinogenicity experiments identified in a comprehensive literature search through September 2000 was analyzed for evidence of hormesis. This database includes lifetime studies of tumorigenic responses in mice, rats, and dogs to exposures to alpha, beta, gamma, neutron, or x-ray radiation. A J-shaped dose response, in the form of a significant decreased response at some low dose followed by a significant increased response at a higher dose, was found in only four datasets from three experiments. Three of these datasets involved the same control animals and two also shared dosed animals; the J shape in the fourth dataset appeared to be the result of an outlier within an otherwise monotonic dose response. A meta-analysis was conducted to determine whether there was an excess of dose groups with decreases in tumor response below that in controls at doses below no-observed-effect levels (NOELs) in individual datasets. Because the probability of a decreased response is generally not equal to the probability of an increased response even in the null case, the meta-analysis focused on comparing the number of statistically significant diminished responses to the number expected, assuming no dose effect below the NOEL. Only 54 dose groups out of the total of 2579 in the database had doses below the dataset-specific NOEL and that satisfied an a priori criterion for sufficient power to detect a reduced response. Among these 54, a liberal criterion for defining a significant decreases identified 15 such decreases, versus 54 × 0.2 = 10.8 expected. The excess in significant reductions was accounted for almost entirely by the excess from neutron experiments (10 observed, 6.2 expected). Nine of these 10 dose groups involved only 2 distinct control groups, and 2 pairs from the 10 even shared dosed animals. Given this high degree of overlap, this small excess did not appear remarkable, although the overlap prevented a formal statistical analysis. A comprehensive post hoc evaluation using a range of NOEL definitions and alternative ways of restricting the data entering the analysis did not produce materially different results. A second meta-analysis found that, in every possible low dose range ([0, d] for every dose, d) of each of the radiation types, the number of dose groups with significantly increased tumorigenic responses was either close to or exceeded the number showing significantly reduced responses. This meta-analysis was considered to be the more definitive one. Not only did it take dose into account by looking for consistent evidence of hormesis throughout defined low-dose ranges, it was also potentially less susceptible to limitations in experimental protocols that would cause individual animals to respond in a non-independent fashion. Overall, this study found little evidence in a comprehensive animal radiation database to support the hormesis hypothesis. However, the ability of the database to detect a hormetic effect was limited both by the small number of dose groups with doses below the range where positive effects have been found in epidemiological studies (≤ 0.1 Gy) and by the limited power of many of these dose groups for detecting a decrease in response.

Health outcomes of low-dose ionizing radiation exposure among medical workers: a cohort study of the Canadian national dose registry of radiation workers.

BACKGROUND: Medical workers can be exposed to low-dose ionizing radiation from various sources. The potential cancer risks associated with ionizing radiation exposure have been derived from cohort studies of Japanese atomic bomb survivors who had experienced acute, high-level exposure. Since such extrapolations are subject to uncertainty, direct information is needed on the risk associated with chronic low-dose occupational exposure to ionizing radiation. OBJECTIVES: To determine the occupational doses of ionizing radiation and examine possible associations with mortality rates and cancer incidence in a cohort of medical workers deriving from the National Dose Registry of Canada (NDR) over the period of 1951-1987. METHODS: Standardized mortality and incidence ratios (SMR and SIR, respectively) were ascertained by linking NDR data for a cohort of 67 562 medical workers (23 580 males and 43 982 females) with the data maintained by the Canadian Mortality, and Cancer Incidence databases. Dosimetry information was obtained from the National Dosimetry Services. RESULTS: During the follow-up period, 1309 incident cases of cancer (509 in males, 800 in females) and 1325 deaths (823 in males, 502 in females) were observed. Mortality from cancer and non-cancer causes was generally below expected as compared to the general Canadian population. Thyroid cancer incidence was significantly elevated both among males and females, with a combined SIR of 1.74 and 90% CI: 1.40-2.10. CONCLUSIONS: The findings confirm previous reports on an increased risk of the thyroid cancer among medical workers occupationally exposed to ionizing radiation. Over the last 50 years, radiation protection measures have been effective in reducing radiation exposures of medical workers to the current very low levels.

Low dose ionizing radiation exposure and cardiovascular disease mortality: cohort study based on Canadian national dose registry of radiation workers.

OBJECTIVES: The purpose of our study was to assess the risk of cardiovascular disease (CVD) mortality in a Canadian cohort of 337 397 individuals (169 256 men and 168 141 women) occupationally exposed to ionizing radiation and included in the National Dose Registry (NDR) of Canada. MATERIAL AND METHODS: Exposure to high doses of ionizing radiation, such as those received during radiotherapy, leads to increased risk of cardiovascular diseases. The emerging evidence of excess risk of CVDs after exposure to doses well below those previously considered as safe warrants epidemiological studies of populations exposed to low levels of ionizing radiation. In the present study, the cohort consisted of employees at nuclear power stations (nuclear workers) as well as medical, dental and industrial workers. The mean whole body radiation dose was 8.6 mSv for men and 1.2 mSv for women. RESULTS: During the study period (1951-1995), as many as 3 533 deaths from cardiovascular diseases have been identified (3 018 among men and 515 among women). In the cohort, CVD mortality was significantly lower than in the general population of Canada. The cohort showed a significant dose response both among men and women. Risk estimates of CVD mortality in the NDR cohort, when expressed as excess relative risk per unit dose, were higher than those in most other occupational cohorts and higher than in the studies of Japanese atomic bomb survivors. CONCLUSIONS: The study has demonstrated a strong positive association between radiation dose and the risk of CVD mortality. Caution needs to be exercised when interpreting these results, due to the potential bias introduced by dosimetry uncertainties, the possible record linkage errors, and especially by the lack of adjustment for non-radiation risk factors.

Lung, liver and bone cancer mortality in Mayak workers.

Workers at the Mayak nuclear facility in the Russian Federation offer the only adequate human data for evaluating cancer risks from exposure to plutonium. Risks of mortality from cancers of the lung, liver and bone, the organs receiving the largest doses from plutonium, were evaluated in a cohort of 17,740 workers initially hired 1948-1972 using, for the first time, recently improved individual organ dose estimates. Excess relative risk (ERR) models were used to evaluate risks as functions of internal (plutonium) dose, external (primarily gamma) dose, gender, attained age and smoking. By December 31, 2003, 681 lung cancer deaths, 75 liver cancer deaths and 30 bone cancer deaths had occurred. Of these 786 deaths, 239 (30%) were attributed to plutonium exposure. Significant plutonium dose-response relationships (p < 0.001) were observed for all 3 endpoints, with lung and liver cancer risks reasonably described by linear functions. At attained age 60, the ERRs per Gy for lung cancer were 7.1 for males and 15 for females; the averaged-attained age ERRs for liver cancer were 2.6 and 29 for males and females, respectively; those for bone cancer were 0.76 and 3.4. This study is the first to present and compare dose-response analyses for cancers of all 3 organs. The unique Mayak cohort with its high exposures and well characterized doses has allowed quantification of the plutonium dose-response for lung, liver and bone cancer risks based on direct human data. These results will play an important role in plutonium risk assessment.

Canadian National Dose Registry of radiation workers: overview of research from 1951 through 2007.

The National Dose Registry (NDR) of Canada is a unique resource for a direct estimation of the potential health risks associated with low doses of ionizing radiation. This is the largest national occupational radiation exposure database, comprising records for about 600,000 nuclear, industrial, medical and dental workers. An analysis of the NDR data based on a cohort of about 200,000 workers first exposed before 1984 and followed through 1987 and 1988 for mortality and cancer incidence, respectively, revealed that the mortality from most causes of death considered was lower than that in the general population, which is typical of occupational cohorts. Although the same was also observed for cancer incidence, there was a significant increase in the incidence of thyroid cancer and melanoma which, however, was not clearly related to radiation exposure. A significant dose-response was found for mortality from all causes, all cancers, lung cancer, cardiovascular diseases, accidents, for incidence of all cancers, cancers of the rectum and lung, leukaemia, all cancers except lung, and all cancers except leukaemia. In addition, in male workers, a significant dose-response was found for the incidence of colon, pancreatic, and testicular cancers. The estimates of cancer risks (mortality and incidence) were higher than those in most other occupational cohorts and in the studies on atomic bomb survivors. The biologically based dose-response models used to describe lung cancer incidence in the NDR showed that for a protracted exposure to low radiation doses there was a significant radiation effect on the promotion and malignant conversion, but not on the initiation stage of carcinogenesis. This stands in contrast to the findings for high-dose acute exposures in A-bomb survivors, where the initiation and possibly promotion were found to be affected by radiation exposure. Evidence of an inverse dose-rate effect (i.e. an increase in the risk with a protraction of a given cumulative dose) was found in the NDR cohort.