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Evaluating the risk decision process.

In order to ensure that risk assessment and risk management serve their purposes efficiently, it is essential to systematically evaluate actual practices. In this overview, it is proposed that such evaluation studies constitute an important field of study that should be recognized as a sub-discipline of regulatory toxicology with its own research issues and its own methodologies. Previous such evaluation studies are summarized. Methods are described that can be used for comparing different risk assessments of one of the same substance, for checking the consistency of harmonized classifications with the available data, for assessing the actual margin of safety (i.e. size of uncertainty factors) in exposure limits, and for comparing different lists of exposure limits. In conclusion, some important problem areas for future evaluation studies are pointed out.

Animals↗

Individual susceptibility to hexavalent chromium of workers of shoe, hide, and leather industries. Immunological pattern of HLA-B8, DR3-positive subjects.

BACKGROUND: This study was designed to examine the effects of hexavalent chromium [Cr(VI)] on the immunological pattern of shoe, hide, and leather industry workers, moving from the hypothesis that some haplotypes (HLA-B8,DR3) can be important hidden risk cofactors. METHODS: Workplaces of 20 firms were monitored for total and respirable dusts and for total and hexavalent chromium. Cr(VI) on materials was also measured. Assay of chromium levels in blood and urine of 44 serological human leukocytes antigen (HLA)-typed workers (20 exposed, 15 HLA-B8,DR3-negative/5-positive and 24 non-exposed, 18 HLA-B8,DR3-negative/6-positive subjects) was performed by atomic absorption, and lymphocyte subsets (FACS-analysis), mitogen-mediate lympho-proliferation ([3H]thymidine incorporation), cytokine levels (ELISA), natural killer (NK) cytotoxic activity (51Cr-release assay) were determined. RESULTS: The environmental parameter levels are lower than threshold limit value-time-weighted average (TLV-TWA); in the materials, the Cr(VI) values exceeded the levels allowed. The peripheral blood mononuclear cells (PBMC) proliferation and the T-helper1 (TH1) cytokine pattern of subjects chronically exposed were significantly raised; addition in vitro of Cr(VI) further stimulated these parameters and in general the entire TH1 system and NK activity. The TH2 system was unaltered. In the HLA-B8,DR3-positive workers, immunologically "low responders", the addition of Cr(VI) in vitro caused a further reduction of the considered parameters in the exposed subjects with a dramatic deficit of the TH1 system. CONCLUSIONS: Results indicate the unsuitability of TLV-TWA as a line of demarcation between safe and dangerous Cr(VI) concentrations and the importance of individual genetic susceptibility for occupational and preventative medicine. In particular, the presence of the HLA-B8,DR3 alleles can represent an important cofactor of immunotoxic susceptibility consequent to chronic low-dose Cr(VI) exposure.

Carcinogens, Environmental↗

The development and implementation of occupational exposure limits in Hong Kong.

The blooming of economy in Hong Kong started in 1950s. People witnessed the change from a rural town to a modern city. It required the participation of a large number of labours. The development of a list of "practical" hygiene standards for control of airborne contaminants in workplaces is important to protect the well beings of those workers. It follows the pace of economic changes, and it takes quite a long while for the current Code of Practice on Control of Air Impurities in workplace environment to be published. There had been a consultation with stakeholders, professional bodies, representatives of trades, and industries as well as other related parties before it was finalized in 2002. Although the Code of Practice comprises just more than 200 chemicals, its application will be monitored and reviewed. In light of new knowledge, it will be updated to ensure the workers could be well protected.

Government Regulation↗

The development and regulation of occupational exposure limits in Korea.

With the institution of the new chemical regulatory framework in 2003, chemicals at the workplace have been classified into five categories; banned substances, permission-required substances, regulated substances, occupational exposure limit set substances, and other generally controlled substances. Currently, there are 698 substances with OELs. As we have come to gain our own experiences in the study and control of chemical hazards at the workplace such as the 2-bromopropane poisoning, OEL setting process has been streamlined. The OELs in Korea, however, remain merely as a recommendation, which does not require all the substances with OELs to be measured at the workplace. Coordination of whole program for hazardous chemicals including workplace measurement, OEL setting process, and enforcement activities is still needed in Korea.

Government Regulation↗

Developing regulations for occupational exposures to health hazards in Malaysia.

In Malaysia exposures in the workplace are regulated under the Factories and Machinery Act (FMA), 1967 and also under the more comprehensive Occupational Safety and Health Act (OSHA) enacted in 1994. With OSHA 1994 the philosophy of legislating safety and health in the workplace changed from one that was very prescriptive and containing detailed technical provisions under FMA, 1967 to one that is more flexible and encourages self-regulation under OSHA 1994. OSHA 1994 is supported by regulations, codes of practices and guidelines to further clarify the provisions in the Act. Under the FMA 1967 emphasis was on safety while with OSHA 1994 there has been equal emphasis on addressing health hazards in the workplace. Regulations for occupational exposures are developed by the Department of Occupational Safety and Health with tripartite and stakeholder consultation. When developing these regulations International Labor Organization Conventions, laws of other countries and occupational exposure standards adopted internationally are reviewed. The government also conducts surveys to collect information on both exposures and health effects in workplaces to have better understanding on specific occupational health problems. Effective law enforcement is crucial in ensuring compliance to safety and health law. The challenge at the moment is to ensure all employers and employees, particularly those in the small and medium enterprises, understand and comply with the provisions stipulated in the legislation.

Government Regulation↗

The development and regulation of occupational exposure limits in Singapore.

Singapore is an island republic in South East Asia with a workforce of about 2.1 million including 0.7 million employed in the manufacturing industry. Singapore's industry is diversified and the main growth sectors include microelectronics, chemical, petrochemical, pharmaceutical, and biomedical sectors. Exposure to chemical hazards is one of the main occupational health problems in the manufacturing sectors. The main roles of government in the protection of workers against safety and health hazards are to set standards and provide a proper infrastructure for industry to self-regulate. The occupation safety and health laws must provide adequate protection of workforce but must not disadvantage local industry in this globally competitive economy. To ensure a level playing field, Singapore's occupational exposure standards are benchmarked against those established in the developed countries. These standards are reviewed regularly to ensure they are realistic and relevant in tandem with worldwide trends. Industry and stakeholders are consulted before any new standards are introduced. In enforcing the laws relating to exposure standards, legal and administrative procedures are followed to ensure fairness and to prevent abuse.

Environmental Monitoring↗

The development and regulation of occupational exposure limits in China.

Of the 700 million workers in China, approximately 200 million workers are potentially exposed to industrial hazards. Although the promulgation and implementation of occupational exposure limits (OELs) in China began in the mid-1950, a systematic approach was not formalized until the formation of the Subcommittee of Occupational Health Standards Setting (SOHSS) in 1981. More recently, the 2002 Occupational Disease Prevention and Control Act of the People's Republic of China created the legislative framework for the development and enforcement of OELs. The SOHSS, whose members are primarily health professionals, is the organization responsible for the development of recommended standards, under the auspices of the Ministry of Health. The philosophy of OEL development of the SOHSS consists of a two-step approach: (1) an initial health-based recommended standard is established based on scientific data, and (2) a final law-based standard takes into consideration both socioeconomic and technological feasibility. Governmental agencies such as the Centers for Diseases Control and Prevention and the Institutes of Public Health Supervision at the state, provincial or municipal levels are charged with the responsibilities of the enforcement of OELs. The process and challenges in the enforcement of OELs are discussed. A comparison is made between selected Chinese OELs and those in other countries. The OELs for benzene and industrial dusts (including silica) are discussed in some detail.

Carcinogens, Environmental↗

The development and regulation of occupational exposure limits in Taiwan.

The occupational exposure limits (OELs) in Taiwan was promulgated in 1974 and has been revised five times since then. Many of the OELs were adopted from the most recent ACGIH TLVs and US OSHA PELs. A total of 483 chemicals were listed in the current Taiwan OELs Standard. The procedures of OELs development in Taiwan include the IOSH organized a recommended exposure limits (RELs) Committee to select the target chemicals and to recommend the RELs through literature review based on the health effects in the first stage, then, the CLA put policy needs, economical and technical feasibility into consideration and set up the final OELs at the second stage. A standard operation manual of RELs Committee has been developed. Based on our experience, several issues including the participation of representatives from a comprehensive spectrum, communication/education and training/enforcement, continuous collection of the local exposure data and health hazard information, use of health risk assessment, consideration of economic, and technical feasibility, as well as the globalization and information and experience sharing are critical in developing the appropriate OELs. Three examples including benzene, crystalline silica, and 2-methoxy ethanol are given to demonstrate the operation of system.

Government Regulation↗

Lead exposure, lead poisoning, and lead regulatory standards in China, 1990-2005.

This article presents a summary of lead exposure levels and lead poisoning at workplaces in China reported in the Chinese medical literature between 1990 and 2005. A comprehensive literature search identified 618 papers reporting lead exposure and lead poisoning data. The data were analyzed in terms of time period, type of industry, size of factory, and task or process. In 2002 the new Occupational Diseases Prevention and Control Act was passed in China, with new provisions specifically for regulatory enforcement. Therefore, a comparison of lead exposure levels and lead poisoning rates before and after the 2002 Act will shed some light on the effectiveness of the new regulation. The reported lead exposure levels covered a wide range; some measurements were in excess of 250 mg/m(3), which was orders-of-magnitude higher than the occupational exposure levels (OELs) for lead in China. The overall arithmetic mean, median, and geometric mean were 0.92, 0.25, and 0.24 mg/m(3), respectively. Approximately 53.7% of the averages reported in the papers were above the national OELs. The data demonstrated that many facilities in the lead industries reported in the literature were not in compliance with the OELs. Similarly, there appeared to be only a minor impact of the 2002 Act on the reduction of occupational lead poisoning in China. The lead poisoning rates reported in the literature were well above 30%. Judging by the lead exposure levels and the lead poisoning rates, the current overall occupational health monitoring system appears inadequate, lacking the necessary enforcement. The 2002 Act, without the necessary enforcement, did not appear to have a major impact on either lead exposures or lead poisoning in China. Much work in enforcing the 2002 Act remains to be done.

China↗

Assessment of airborne asbestos exposure during the servicing and handling of automobile asbestos-containing gaskets.

Five test sessions were conducted to assess asbestos exposure during the removal or installation of asbestos-containing gaskets on vehicles. All testing took place within an operative automotive repair facility involving passenger cars and a pickup truck ranging in vintage from late 1960s through 1970s. A professional mechanic performed all shop work including engine disassembly and reassembly, gasket manipulation and parts cleaning. Bulk sample analysis of removed gaskets through polarized light microscopy (PLM) revealed asbestos fiber concentrations ranging between 0 and 75%. Personal and area air samples were collected and analyzed using National Institute of Occupational Safety Health (NIOSH) methods 7400 [phase contrast microscopy (PCM)] and 7402 [transmission electron microscopy (TEM)]. Among all air samples collected, approximately 21% (n = 11) contained chrysotile fibers. The mean PCM and phase contrast microscopy equivalent (PCME) 8-h time weighted average (TWA) concentrations for these samples were 0.0031 fibers/cubic centimeters (f/cc) and 0.0017 f/cc, respectively. Based on these findings, automobile mechanics who worked with asbestos-containing gaskets may have been exposed to concentrations of airborne asbestos concentrations approximately 100 times lower than the current Occupational Safety and Health Administration (OSHA) Permissible Exposure Limit (PEL) of 0.1 f/cc.

Air Pollutants, Occupational↗

Benzene exposure in the shoemaking industry in China, a literature survey, 1978-2004.

This article presents a summary of benzene exposure levels in the shoemaking industry in China reported in the Chinese medical literature between 1978 and 2004. A comprehensive search identified 182 papers reporting such exposure data. These papers could be classified into two categories: benzene poisoning case reports and industrial hygiene surveys. From each paper, the following information was abstracted whenever available: location and year of occurrence, occupation and/or task involved, benzene content in adhesives/solvents, work environment, working conditions, working hours, diagnosis, and air monitoring data of benzene. A total of 333 benzene measurements (88 averages, 116 minimums, 129 maximums) in the shoemaking industry were reported in the 182 papers identified. The data were analyzed in terms of geographical location, time period, type of ownership (state, township, or foreign), type of report (benzene poisoning reports vs. industrial hygiene surveys), and job title (work activity) or process. The reported data covered a wide range; some measurements were in excess of 4500 mg/m(3). Thirty-five percent of the reported benzene concentrations were below 40 mg/m(3), which was the national occupational exposure limit (OEL) for benzene between 1979 and 2001. The remaining 65% measurements, which exceeded the national OEL in effect at the time, and were distributed as follows: 40-100 mg/m(3), 11%; 100-300 mg/m(3), 21%; 300-500 mg/m(3), 13%; and 500+ mg/m(3), 20%. However, only 24% of the reported measurements after 2002 were below 6 mg/m(3), i.e., Permissible Concentration-Time Weighted Average (PC-TWA) and 10 mg/m(3), i.e., Permissible Concentration-Short Term Exposure Limit (PC-STEL), the newly amended benzene OELs in effect after May 2002. The data demonstrated that the majority of the facilities in the shoemaking industry reported in the literature were not in compliance of the OEL for benzene in effect at the time. Overall, the data show a clear downward trend of benzene exposure levels over the years, particularly after the introduction of the new lower OEL in 2002. Even though substantially lower when compared to levels in the past, current benzene exposure measurements from the literature review suggest that many facilities in the shoemaking industry in China have benzene concentrations that are still above the new OEL. The reported data, stratified by job, year and survey reason, can be used as part of the information and analysis for developing a job-exposure matrix in retrospective exposure assessment and thus may be part of the information used in developing historical exposure estimates in epidemiologic studies of shoe workers.

Air Pollutants, Occupational↗

General aspects of peptide selectivity towards lipid bilayers and cell membranes studied by variation of the structural parameters of amphipathic helical model peptides.

Model compounds of modified hydrophobicity (Eta), hydrophobic moment (mu) and angle subtended by charged residues (Phi) were synthesized to define the general roles of structural motifs of cationic helical peptides for membrane activity and selectivity. The peptide sets were based on a highly hydrophobic, non-selective KLA model peptide with high antimicrobial and hemolytic activity. Variation of the investigated parameters was found to be a suitable method for modifying peptide selectivity towards either neutral or highly negatively charged lipid bilayers. Eta and mu influenced selectivity preferentially via modification of activity on 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC) bilayers, while the size of the polar/hydrophobic angle affected the activity against 1-palmitoyl-2-oleoylphosphatidyl-DL-glycerol (POPG). The influence of the parameters on the activity determining step was modest in both lipid systems and the activity profiles were the result of the parameters' influence on the second less pronounced permeabilization step. Thus, the activity towards POPC vesicles was determined by the high permeabilizing efficiency, however, changes in the structural parameters preferentially influenced the relatively moderate affinity. In contrast, intensive peptide accumulation via electrostatic interactions was sufficient for the destabilization of highly negatively charged POPG lipid membranes, but changes in the activity profile, as revealed by the modification of Phi, seem to be preferentially caused by variation of the low permeabilizing efficiency. The parameters proved very effective also in modifying antimicrobial and hemolytic activity. However, their influence on cell selectivity was limited. A threshold value of hydrophobicity seems to exist which restricted the activity modifying potential of mu and Phi on both lipid bilayers and cell membranes.

Anti-Bacterial Agents↗

Long-term, low-level exposure of guinea pigs and marmosets to sarin vapor in air: lowest observable effect level.

Realistic scenarios for low-level exposure to nerve agents will often involve exposures over several hours to extremely low doses of agent. In order to expose animals to the lowest controllable concentrations of agent and to increase exposure times until a lowest observable effect level (LOEL) becomes measurable, a validated system was developed for exposing conscious animals to 0.05-1.0 microg/m(3) (8-160 ppt) of sarin and other nerve agents. Based on cold trapping of sarin from the exposure air, the concentration could be measured semicontinuously, at 4-min time intervals by means of gas chromatography. We found that the LOEL upon a 5-h whole body exposure of guinea pigs and marmosets to sarin vapor corresponds with the measurement of an internal dose by means of fluoride-induced regeneration of sarin from phosphylated binding sites in plasma, mostly BuChE. For guinea pigs the LOEL was observed at Ct = 0.010 +/- 0.002 mg/min/m(3), whereas a Ct of 0.04 +/- 0.01 mg/min/m(3) was established for the LOEL in marmosets. These levels are several orders of magnitude lower than those based on classical measurement of depressed cholinesterase activities. At low exposure levels of guinea pigs and marmosets (< or =1 microg/m(3)), a reasonable linearity was observed between exposure dose and internal dose. The data were addressed in the light of the recently recommended occupational exposure limits to sarin for workers without respiratory protection, which suggests that the exposure limits should be reconsidered if the slightest inhibition of cholinesterases should be prevented.

Animals↗

Induction of the P450 reporter gene system bioassay by polycyclic aromatic hydrocarbons in Ulsan Bay (South Korea) sediments.

Polycyclic aromatic hydrocarbons (PAHs) and induction of the P450 reporter gene system (RGS) for 6- and 16-h exposure periods were determined in organic extracts of Ulsan Bay (South Korea) sediments to assess the utility of this bioassay as a screening tool for PAH contamination. The sum of the concentrations of 23 individual PAHs in 30 sediment samples (sigma PAH) based on GC-MS analysis ranged from 0.05 to 6.1 micrograms/g dry wt. P450 RGS fold induction ranged from 4.0 to 320 micrograms/g based on benzo[a]pyrene toxic equivalents (BaPEq). P450 RGS BaPEq and the 'chemical BaPEq', defined as the sum of the products of individual PAH concentrations and pre-determined toxic equivalency factors, exhibited very strong positive correlations with sigma PAH (r2 > 0.90; P < 0.001). Fold induction did not increase (and in some cases decreased) after the optimal incubation period (6 h) for PAHs, indicating that other compounds known to induce the P450 RGS (e.g. chlorinated organics) were not present at levels effecting significant induction. This was supported by GC-ECD analysis where non-ortho and mono-ortho polychlorinated biphenyls (PCBs) known to be strong P450 RGS inducers were found to be at very low or non-detectable levels in samples with the highest P450 RGS responses. The profound difference in PAH profiles for the two most contaminated sites suggested that this assay is especially sensitive for selected PAHs with greater than four rings. Combined with previous results, the P450 RGS shows promise as a useful screening tool for predicting deleterious biological effects resulting from CYP1A1-inducing, sediment-associated chemicals, particularly high molecular weight PAHs.

Biological Assay↗

Airborne asbestos concentration from brake changing does not exceed permissible exposure limit.

The use in the past, and to a lesser extent today, of chrysotile asbestos in automobile brake systems causes health concerns among professional mechanics. Therefore, we conducted four separate tests in order to evaluate an auto mechanic's exposure to airborne asbestos fibers while performing routine brake maintenance. Four nearly identical automobiles from 1960s having four wheel drum brakes were used. Each automobile was fitted with new replacement asbestos-containing brake shoes and then driven over a predetermined public road course for about 2253 km. Then, each car was separately brought into a repair facility; the brakes removed and replaced with new asbestos-containing shoes. The test conditions, methods, and tools were as commonly used during the 1960s. The mechanic was experienced in brake maintenance, having worked in the automobile repair profession beginning in the 1960s. Effects of three independent variables, e.g., filing, sanding, and arc grinding of the replacement brake shoe elements, were tested. Personal and area air samples were collected and analyzed for the presence of fibers, asbestos fibers, total dust, and respirable dust. The results indicated a presence in the air of only chrysotile asbestos and an absence of other types of asbestos. Airborne chrysotile fiber exposures for each test remained below currently applicable limit of 0.1 fiber/ml (eight-hour time-weighted average).

Air Pollutants, Occupational↗

Mathematical modelling and quantitative methods.

The present review reports on the mathematical methods and statistical techniques presently available for hazard characterisation. The state of the art of mathematical modelling and quantitative methods used currently for regulatory decision-making in Europe and additional potential methods for risk assessment of chemicals in food and diet are described. Existing practices of JECFA, FDA, EPA, etc., are examined for their similarities and differences. A framework is established for the development of new and improved quantitative methodologies. Areas for refinement, improvement and increase of efficiency of each method are identified in a gap analysis. Based on this critical evaluation, needs for future research are defined. It is concluded from our work that mathematical modelling of the dose-response relationship would improve the risk assessment process. An adequate characterisation of the dose-response relationship by mathematical modelling clearly requires the use of a sufficient number of dose groups to achieve a range of different response levels. This need not necessarily lead to an increase in the total number of animals in the study if an appropriate design is used. Chemical-specific data relating to the mode or mechanism of action and/or the toxicokinetics of the chemical should be used for dose-response characterisation whenever possible. It is concluded that a single method of hazard characterisation would not be suitable for all kinds of risk assessments, and that a range of different approaches is necessary so that the method used is the most appropriate for the data available and for the risk characterisation issue. Future refinements to dose-response characterisation should incorporate more clearly the extent of uncertainty and variability in the resulting output.

Animals↗

Inhaled nitric oxide: are the safety issues being addressed?

Interest in the therapeutic uses of Nitric Oxide (NO) has gathered pace over the last decade. It is no exaggeration for the UK Guidelines on the Use of Inhaled Nitric Oxide (Cuthbertson et al. 1997) to say that 'the use of inhaled nitric oxide in the UK has become commonplace'. The index of the third edition (1990) of TE Oh's notable Intensive Care Manual carries no reference to it. Yet, from its origins in obscure research, the discovery of NO has promised the development of therapies which might include the revolutionary transformation of approaches to the treatment of septic shock. It also holds promise in the treatment of acute respiratory distress syndrome (ARDS). It is in this context that this discussion will seek to raise fundamental questions about the health and safety aspects of this substance.

Administration, Inhalation↗