Occupational toxicology and the control of exposure to pharmaceutical agents at work

BACKGROUND: The pharmaceutical industry employs >350 000 people worldwide in operations including research and development (R&D), manufacturing, sales and marketing. Workers employed in R&D and manufacturing sectors are potentially exposed to drug substances in the workplace that are designed to modify physiology and also to chemical precursors that are potentially hazardous to health. Pharmaceutical workers are at risk from adverse health effects, including occupational asthma, pharmacological effects, adverse reproductive outcomes and dermatitis. AIM: This study aimed to describe the approaches taken by pharmaceutical companies for identifying and communicating potential adverse health effects that may result from workplace exposures and in setting 'in-house' exposure control limits and to highlight the challenges in controlling workplace exposures to increasingly potent compounds. METHOD: The literature was reviewed by searching the Medline and HSELine databases. RESULTS: The findings are presented in five sections, covering: test methods and approaches to occupational toxicology; hazard communication; approaches to setting health-based occupational exposure limits for pharmaceutically active agents; recent approaches to risk control; and occupational hygiene and exposure controls. CONCLUSION: Significant efforts have been directed at predicting and evaluating potential occupational health hazards in the pharmaceutical industry. The pharmaceutical industry has provided leadership in controlling exposure to hazardous substances. Much of this work has been driven by a real need to control occupational exposures to substances that can have profound adverse health effects in exposed employees and that are becoming increasingly more potent.     

Occupational skin conditions in the food industry

The study presents the findings of a questionnaire survey of skin conditions in a selective sample of the UK food industry, covering companies who employ occupational physicians. The mean incidence of skin conditions in food manufacturing operations was 2103 per million employees per annum. The mean incidence in retail or catering organizations was 1414 per million employees per annum.     

Estimated research and development costs of rotavirus vaccines

Diseases like rotavirus afflict both upper- and lower-income countries, but most serious illnesses and deaths occur among the latter. It is a vital public health issue that vaccines for these types of global diseases can recover research and development (R&D) costs from high-priced markets quickly so that manufacturers can offer affordable prices to lower-income nations. Cost recovery depends on how high R&D costs are, and this study attempts to replace high, unverified estimates with lower, more verifiable estimates for two new vaccines, RotaTeq (Merck) and Rotarix (GlaxoSmithKline or GSK), based on detailed searches of public information and follow-up interviews with senior informants. We also offer a new perspective on “cost of capital” as a claim for recovery from public bodies. Our estimates suggest that companies can recover all fixed costs quickly from affluent markets and thus can offer these vaccines to lower-income countries at prices they can afford. Better vaccines are a shared project between companies and public health agencies; greater transparency and consistency in reporting of R&D costs is needed so that fair prices can be established.     

Sustainable vaccine manufacturing in low- and middle-Income countries

The sustainable manufacturing of vaccines in developing countries is critical to increasing equitable access to vaccines and pandemic preparedness globally. Sustainable manufacturing requires that organizations engaged in the development, production and supply of vaccines have viable business models and incentives to manufacture vaccine products.The expanding manufacturing capabilities and capacities of developing countries vaccine manufacturers (DCVMs) are increasingly positioning these organizations to meet the national and regional public health needs in developing countries; however, key industry challenges such as regulatory barriers, low prices and demand uncertainty for vaccine products, and limited R&D funding threaten the long-term viability of vaccine manufacturers.This study assesses the technical capabilities, manufacturing capacities, and aspirational plans of DCVMs, exemplifying the business models and strategies undertaken to sustainably manufacture vaccines in developing countries. The public health importance of a healthy vaccine industry which enables manufacturers is discussed throughout.Vaccine manufacturers reported diverse product portfolios and R&D pipelines and utilized an array of vaccine technology platforms. Large manufacturing capacities were reported, a critical factor in manufacturers achieving economies of scale and supplying large volumes of vaccine doses to the world’s most populous regions. Partnerships and collaboration within the industry and with international organizations along the vaccine value-chain were cited with high frequency. Manufacturers also reported aspirational plans to enter new markets, acquire new technologies and invest in the development of novel and improved vaccines.As DCVMs aim to have an increasing impact on the global vaccine ecosystem, a coordinated multi-stakeholder approach is required alleviate critical industry barriers to ensure that all efforts produce vaccines are sustainable and enable developing countries to realize the public health benefit of vaccines.     

Dehydroabietic acid as a biomarker for exposure to colophony

BACKGROUND: Colophony (rosin) is a natural product derived from the resin of coniferous trees with many industrial applications including soldering fluxes. Exposure to colophony fume through soldering is one of the leading causes of occupational asthma in the UK. AIMS: To assess occupational exposure to colophony from solder fume at selected workplaces in the UK and to investigate the use of dehydroabietic acid (DHA) as a biomarker of exposure. METHODS: Six companies in the UK electronics industry were visited and occupational hygiene assessments of extent and control of exposure to rosin-based solder flux fume were undertaken. Urine samples were analysed for one of the main constituents of rosin, DHA. RESULTS: There was a positive linear relationship between airborne exposure to solder fume and urinary DHA level. The levels of urinary DHA measured in UK workers were significantly lower than those previously measured in African workers because of the use of appropriate exposure control measures, for example, local exhaust ventilation with fixed ducting and flexible hose, tip extraction, etc. It is suggested that good occupational hygiene practice would result in urinary DHA levels of <3 micromol/mol creatinine in a post-shift urine sample. CONCLUSIONS: Urinary DHA is a valid biomarker of exposure to colophony in solder fume. Further work on the excretion kinetics of urinary DHA, the possibility of skin absorption and further occupational hygiene surveys would be beneficial.     

Biological monitoring and exposure to mercury

Occupational health professionals' interest in controlling mercury (Hg) exposure, and the use of biological monitoring in this context, has been ongoing for a number of years. Evidence from urinary Hg results in a number of UK firms who have undertaken some form of biological monitoring or occupational health surveillance suggest that exposure has decreased over the last 10-15 years. This decrease precedes the establishment in the UK of an advisory biological monitoring guidance value (HGV) for urinary Hg and the production of updated medical guidance from the Health & Safety Executive on Hg exposure (MS12 1996). This latter document recommends a urinary sampling interval for urinary Hg of between 1 and 3 months, which is consistent with the reported toxicokinetics of Hg excretion, but we highlight that urinary Hg represents integrated exposure over many previous months. Mercury is a recognized nephrotoxin and MS12 1996 mentions the use of regular dipstick protein estimations. We review our experience of investigating proteinuria and enzymuria in a large-scale cross-sectional occupational study. The incidence of Hg-induced renal disease is probably very rare at current exposure levels. Therefore acceptance of a high false-positive rate of proteinuria not related to Hg exposure needs to be considered in any urinary protein testing regime of Hg workers. The establishment of an HGV for urinary Hg has raised questions about the uncertainty associated with a urinary Hg result, including factors such as diurnal variation, whether urine correction by creatinine or specific gravity is preferable and the possibility of non-occupational sources of Hg contributing significantly towards breaching the HGV. Correction of urinary Hg results by creatinine or specific gravity and the use of a fixed sampling time, such as the beginning or end of the day, substantially reduce the uncertainty in a urinary Hg measurement. But even with good laboratory precision, an individual with a true urinary Hg excretion of 20 nmol/mmol creatinine could supply urine samples of between 14 and 26 nmol/mmol creatinine. The influence of dietary sources in the UK contributing to urinary Hg values approaching or exceeding the HGV is unlikely. The use of tribal or ethnic cosmetics and remedies needs to be considered if a urinary Hg result looks inappropriately high, as some such preparations have been found to contain Hg and can be absorbed through the skin. The ability of excessive chewers or teeth grinders who have a large number of dental amalgam fillings to breach the urinary HGV in the absence of substantial occupational Hg exposure has been reported in a few Scandanavian studies. We report here a likely case of this phenomenon. Since the establishment of the HGV, our biological monitoring Hg data from a number of industry sectors using inorganic or metallic Hg have suggested that a minority of samples (13%) are still greater than the HGV.     

Is occupational dermatitis being taken seriously by UK industries?

Occupational dermatitis is a considerable burden but little is documented concerning industry response to this. A postal questionnaire survey of 1,100 UK companies was conducted to investigate skin care provision. The response rate was 51%. The person primarily responsible for health and safety had a professional qualification in only 34% of responding companies. In all, 75% of companies responded that they were required to conduct COSHH risk assessments and, of these, 71% mentioned skin hazards. Only 27% of companies had a skin care policy but 71% had procedures requiring glove use. Seventy-seven per cent of companies did not conduct regular skin checks. Twenty-six per cent had either been aware of a skin problem in the workforce in the last 12 months or had had to modify work practices. Improvement of skin care in UK industry could be facilitated by the establishment of a minimum recommended training qualification; assistance with compliance with COSHH legislation; and guidelines to design and implement a skin policy, provide worker protection and detect skin problems.     

Nanotechnology and the occupational physician

Nanoparticles differ from the same material at larger scale in chemical and physical properties. Evidence from studies of fibres leads to the conclusion that inhalation of nanotubes could be dangerous and should be regulated. Air pollution research has suggested that particles may be more toxic to cells at the nanoscale. At present the marketing of nanoparticles is advancing more rapidly than research into their safety and toxicology, and one serious inhalation episode has been reported in Germany from apparent use of a nanoproduct. This rapidly developing industry will make an impact on the work of occupational physicians, first in universities and small concerns but later more widely. The future safety of workers and consumers is dependent on research into hazard and risk, an area in which the UK and most other countries are dragging their feet. However, a resource, the Safety of Nanomaterials Interdisciplinary Research Consortium, has been established in the UK to assist those active in this field.     

A review of selected engineered nanoparticles in the atmosphere: sources, transformations, and techniques for sampling and analysis

A state-of-the-science review was undertaken to identify and assess sampling and analysis methods to detect and quantify selected nanomaterials (NMs) in the ambient atmosphere. The review is restricted to five types of NMs of interest to the Office of Research and Development Nanomaterial Research Strategy (U.S. Environmental Protection Agency): cerium oxide, titanium dioxide, carbon nanostructures (carbon nanotubes and fullerenes), zero-valent iron, and silver nanoparticles. One purpose was determining the extent to which present-day ultrafine sampling and analysis methods may be sufficient for identifying and possibly quantifying engineered NMs (ENMs) in ambient air. Conventional sampling methods for ultrafines appear to require modifications. For cerium and titanium, background levels from natural sources make measurement of ENMs difficult to quantify. In cases where field studies have been performed, identification from bulk analysis samples have been made. Further development of methods is needed to identify these NMs, especially in specific size fractions of ambient aerosols.     

The complexity and cost of vaccine manufacturing – An overview

As companies, countries, and governments consider investments in vaccine production for routine immunization and outbreak response, understanding the complexity and cost drivers associated with vaccine production will help to inform business decisions. Leading multinational corporations have good understanding of the complex manufacturing processes, high technological and R&D barriers to entry, and the costs associated with vaccine production. However, decision makers in developing countries, donors and investors may not be aware of the factors that continue to limit the number of new manufacturers and have caused attrition and consolidation among existing manufacturers. This paper describes the processes and cost drivers in acquiring and maintaining licensure of childhood vaccines. In addition, when export is the goal, we describe the requirements to supply those vaccines at affordable prices to low-resource markets, including the process of World Health Organization (WHO) prequalification and supporting policy recommendation. By providing a generalized and consolidated view of these requirements we seek to build awareness in the global community of the benefits and costs associated with vaccine manufacturing and the challenges associated with maintaining consistent supply. We show that while vaccine manufacture may prima facie seem an economic growth opportunity, the complexity and high fixed costs of vaccine manufacturing limit potential profit. Further, for most lower and middle income countries a large majority of the equipment, personnel and consumables will need to be imported for years, further limiting benefits to the local economy.     

Demonstrating the economic value of occupational health services

Many large companies operate some form of occupational health service (OHS). More companies now require specific evaluative information to justify the continued provision of an in-house OHS. This is in the face of increased pressure to control costs, combined with an awareness that the service itself can induce activity (supplier-induced demand) and could be substituted with health care provided or even funded outside the company. The lack of routinely collected data and the conceptual difficulty in defining and measuring the outcomes of an OHS provide challenges for economic evaluation. A purely human capital approach, where people are valued by their wage rates, is likely to be insufficient, since OHSs have multiple objectives. These objectives include fulfilling statutory obligations, contributing to the creation of a culture of partnership, reduction of potential costs to the company (sickness benefit, production loss, poor performance, litigation, insurance) and providing a suitable environment for the cost-effective reduction of the social and health service costs of illness at work. Evidence is needed to quantify some of these arguments and demonstrate to decision makers the value generated by OHSs. The aim of this paper is to consider the practicality of different economic evaluation methodologies, specifically cost models, contingent valuation (willingness-to-pay) and development of OHS-specific outcome measures. In considering different approaches, we present the results of our research in two UK companies.     

Perception and provision of occupational health services in the UK

BACKGROUND: There is difficulty in defining occupational health services among stakeholders of the service. Concurrently, there are concerns about the state of occupational health provision in the UK. AIMS: To determine stakeholders' perception of the services that occupational health encompasses and the level as well as the rationale behind the provision of these services. METHODS: The research was undertaken as a postal questionnaire survey of the FTSE 350 companies and selected public sector organizations in the UK. This was followed up by telephone calls to a random selection of non-respondents to obtain non-respondent data. RESULTS: There is a difference in opinion among managers and occupational health professionals about the services provided by occupational health. Taking into account non-respondent data to partially adjust for overestimation biases, the level of provision of occupational health services among the FTSE 350 companies is 69% and in public sector organizations is 95%, giving an average provision of 72%. Sixteen per cent of respondents thought there was a trend towards outsourcing of services. The most frequently cited reason for provision of an occupational health service was that it was for the benefit of employees. CONCLUSIONS: There remains room for improvement in the level of occupational health services provision in large UK private sector organizations. By bridging the gap between the different stakeholders' perceptions of the remit and benefits of the service, a higher level of provision in the private sector similar to that of public sector organizations can be achieved.     

A Review of Selected Engineered Nanoparticles in the Atmosphere: Sources,Transformations, and Techniques for Sampling and Analysis

Abstract

A state-of-the-science review was undertaken to identify and assess sampling and analysis methods to detect and quantify selected nanomaterials (NMs) in the ambient atmosphere. The review is restricted to five types of NMs of interest to the Office of Research and Development Nanomaterial Research Strategy (US Environmental Protection Agency): cerium oxide, titanium dioxide, carbon nanostructures (carbon nanotubes and fullerenes), zero-valent iron, and silver nanoparticles. One purpose was determining the extent to which present-day ultrafine sampling and analysis methods may be sufficient for identifying and possibly quantifying engineered NMs (ENMs) in ambient air. Conventional sampling methods for ultrafines appear to require modifications. For cerium and titanium, background levels from natural sources make measurement of ENMs difficult to quantify. In cases where field studies have been performed, identification from bulk analysis samples have been made. Further development of methods is needed to identify these NMs, especially in specific size fractions of ambient aerosols.     

Incidence by occupation and industry of work-related skin diseases in the United Kingdom, 1996-2001

BACKGROUND: Work-related skin disease is common but few cases are documented in statutory reports or disability systems. Voluntary reporting by specialist physicians provides more complete information. AIMS: To summarize incidence rates of work-related skin diseases reported by consultant dermatologists and occupational physicians, with emphasis on contact and allergic dermatitis by occupation and industry. METHODS: Cases reported in 1996-2001 to the EPIDERM and OPRA national surveillance schemes were analysed by causal agent, occupation and industry, with incidence rates calculated against appropriate denominators. RESULTS: Average annual incidence rates based on data from dermatologists were 97 per million overall, 74 for contact dermatitis and 14 for neoplasia. The corresponding rates for occupational physicians were 623 overall, 510 and 2, respectively. For infective disease, the rates for occupational physicians were 28 compared to 2 for dermatologists. Contact dermatitis was most frequently attributed to rubber chemicals, soaps and cleaners, wet work, nickel and acrylics; most cases of contact urticaria were attributed to rubber chemicals or foods and flour. The pattern of incidence rates by occupation and industry was complex, but correlated with the probable type of exposure. Rates of contact dermatitis were highest among skilled workers in the petrochemical and rubber and plastic manufacturing industries, with machine operators and technical workers in metal and automotive industries also at increased risk. High proportions of cases attributed to rubber chemicals were in nurses and technicians in the health and social services. CONCLUSIONS: These findings identify jobs and types of work where contact with causal agents is common and potentially preventable.     

Regulatory review time and pharmaceutical research and development

In the United States, all newly developed drugs undergo a lengthy review process conducted by the US Food and Drug Administration (FDA). These regulatory delays have direct immediate costs for drug manufacturers and patients waiting for treatment. Under certain market conditions, regulatory delays may also affect future research and development (R&D) strategies of pharmaceutical companies. To estimate the magnitude of this effect, we match data on drugs in the development pipeline in 2006 to data that we collect on FDA review times for all drugs approved between 1999 and 2005. Employing a rich and novel set of controls that affect drug R&D decisions and, potentially, regulatory review lags, we find that on average, three additional months of delay result in one fewer drug in development in that drug category. Our results suggest that the length of the regulatory delay matters for pharmaceutical firms' R&D decisions and that the firms are likely unable to pass on these costs onto consumers.     

Characterization of cerium oxide nanoparticles-part 2: nonsize measurements

Part 1 (see companion paper) of the present study discussed the application of a multimethod approach in characterizing the size of cerium oxide nanoparticles (NPs). However, other properties less routinely investigated, such as shape and morphology, structure, chemical composition, and surface properties, are likely to play an important role in determining the behavior, reactivity, and potential toxicity of these NPs. The present study describes the measurement of the aforementioned physicochemical properties of NPs (applied also to nanomaterials [NMs]) compared with micrometer particles (MPs). The authors use a wide range of techniques, including high resolution-transmission electron microscopy, scanning electron microscopy, atomic force microscopy, X-ray diffraction, X-ray energy dispersive spectroscopy, electron energy loss spectroscopy, X-ray photoelectron spectroscopy, and electrophoresis, and compare these techniques, their advantages, and their limitations, along with recommendations about how best to approach NM characterization, using an application to commercial cerium oxide NPs and MPs. Results show that both cerium oxide NPs and MPs are formed of single polyhedron or truncated polyhedron crystals. Cerium oxide NPs contain a mixture of Ce(3+) and Ce(4+) cations, whereas the MPs contain mainly Ce(4+) , which is potentially important in understanding the toxicity of cerium oxide NPs. The isoelectric point of cerium oxide NPs was approximately pH 8, which explains their propensity to aggregate in aqueous media (see companion paper).     

The feasibility of conducting occupational epidemiology in the UK

A postal survey was carried out of 1,000 UK companies to collect information about employee biographical and work history records. The overall response rate was 46%. All companies collected surname, forenames, address, date of birth and National Insurance number--information needed for cross-sectional studies. Other biographical details such as maiden name and National Health Service number were collected less often, which could increase the cost and difficulty of tracing ex-employees. Seventy per cent reported destroying their records within 10 years of an employee leaving, rising to 82% for companies with fewer than 100 employees. The destruction of employee records creates problems for historical cohort studies and case-control studies, and may hamper ex-employees trying to claim benefit for occupational-related illness. If the scope of future occupational epidemiology is to be improved, guidelines for the collection and retention of the data required must be developed and industry encouraged to participate.     

Incidence of occupational skin conditions in a food manufacturing company: results of a health surveillance programme

BACKGROUND: The food industry has been associated with a high risk of work-related skin problems. Aim To examine the incidence of work-related skin conditions and the likely causative agents in a single large food company. METHOD: Analysis of a health surveillance programme, conducted over a 7 year period, in a food company with 21 000 employees working in diverse manufacturing processes. RESULTS: The mean incidence of skin conditions, taking all of the different food manufacturing operations together, was 1310 per million employees per annum. The mean incidence was greatest in the manufacturing sector whose operations involved chilled or frozen product (3180 per million employees per annum). Most of the cases reported (184/192 = 96%) were due to primary irritant dermatitis. The two commonest suspected causes of the dermatitis were contact with ingredients and hand washing. Taken together, these factors accounted for 58% of all cases. Although the wearing of gloves is often considered necessary to prevent dermatitis from exposure to ingredients and to lessen the need for hand washing, this factor itself was responsible for 9% of all cases. CONCLUSION: Analysis of a company health surveillance scheme showed the average incidence of work-related skin problems to be lower than previously reported in the food industry.     

Hepatitis B transmission through blood and body fluids exposure of school personnel

BACKGROUND: Hepatitis B transmission from students to members of staff has been documented in schools, particularly nurseries and day care centres. AIMS: To investigate the frequency of exposure to blood and other body fluids within day schools and to document practices adopted by school personnel to avoid direct contact and decontaminate the environment. METHODS: Questionnaire survey among 21 public day schools in Malta. RESULTS: Episodes of significant blood exposure were rare, occurring at frequencies of 0.071 [95% confidence interval (CI): 0-0.148] incidents per thousand student days. Contact with larger volumes of other body fluids, namely urine and vomitus, was more likely: 0.12 (95% CI: 0.008-0.383) and 0.088 (95% CI: 0.048-0.128) episodes per 1000 student days, respectively. School personnel generally used correct personal protective equipment, particularly gloves, in cases of contact with blood and body fluids. Environmental disinfection methods varied considerably with only 38% of schools (95% CI: 21-59%) using recommended hypochlorite preparations. CONCLUSIONS: Exposure to quantities of blood sufficient to result in HBV transmission in day schools is rare. Emphasis should be placed on risk assessment at individual school level, concentrating on correct management of body fluid exposures through effective staff education.     

Building local research and development capacity for the prevention and cure of neglected diseases: the case of India.

This paper examines the proposal to build research and development (R&D) capabilities for dealing with neglected infectious and tropical diseases in countries where they are endemic, as a potentially cost- and time-effective way to fill the gap between the supply of and need for new medicines. With reference to the situation in India, we consider the competencies and incentives needed by companies so that their strategy can be shifted from reverse engineering of existing products to investment in R&D for new products. This requires complex reforms, of which the intellectual property rights agreement is only one. We also consider whether Indian companies capable of conducting research and development are likely to target neglected diseases. Patterns of patenting and of R&D, together with evidence from interviews we have conducted, suggest that Indian companies, like multinational corporations, are likely to target global diseases because of the prospect of much greater returns. Further studies are required on how Indian companies would respond to push and pull incentives originally designed to persuade multinational corporations to do more R&D on neglected diseases.