The assessment of adverse effects on the health on professional workers potentially exposed to hazardous substances during their manufacturing has become a key activity for HSE (Health, Safety and Environment) of all chemical (including pharmaceutical) companies since years (at least 15/20). The progressive demand to determine such evaluation is due to many reasons. In particular:
- A general higher sensitivity of companies and deeper legal liability due to the long application of European Union and USA rules regarding the safety of workplace;
- A deeper knowledge of the hazardous profile of handled chemicals due to application of REACH and related regulations such as biocide, agrochemical, detergents, etc. This is mainly referred to chemical industries when manipulating CMRs (Carcinogenic, Mutagenic and Toxic for Reproduction substances) or highly toxic substances such as sensitizers and/or endocrine disruptors among others;
- The progressive increase in the pharmaceutical production of the so called “High Potency Drugs” (HAPI) which are often, not always, accompanied by a certain toxicological profile which impose to implement containment measures to reduce exposure and consequent health risks.
Many companies have already developed their own policy regarding the evaluation of worker health and related surveillance on the basis of international (EU level/USA level) and National regulations/directives.
The European Framework Directive on Safety and Health at Work (Directive 89/391 EEC) adopted in 1989 was a substantial milestone in improving safety and health at work. It guarantees minimum safety and health requirements throughout Europe while Member States are allowed to maintain or establish more stringent measures.
The Directive 89/391 – OSH “Framework Directive” of 12 June 1989 on the introduction of measures to encourage improvements in the safety and health of workers at work is the starting point of all norms about the workplace safety.
In 1989 some provisions of the Framework Directive brought about considerable innovation including the following:
- The term ‘working environment’ was set in accordance with International Labour Organization (ILO) Convention No. 155 and defines a modern approach taking into account technical safety as well as general prevention of ill-health.
- The Directive aims to establish an equal level of safety and health for the benefit of all workers (the only exceptions are domestic workers and certain public and military services).
- The Directive obliges employers to take appropriate preventive measures to make work safer and healthier.
- The Directive introduces as a key element the principle of risk assessment and defines its main elements (e.g. hazard identification, worker participation, introduction of adequate measures with the priority of eliminating risk at source, documentation and periodical re-assessment of workplace hazards).
- The new obligation to put in place prevention measures implicitly stresses the importance of new forms of safety and health management as part of general management processes.
The Framework Directive had to be transposed into national law by the end of 1992. The consequences of the transposition on national legal systems varied across Member States. In some Member States, the Framework Directive had considerable legal consequences due to inadequate national legislation while in others no major adjustments were necessary.
In 2004 the European Commission issued a Communication (COM (2004) 62) on the practical implementation of the provisions of same of the directives, namely 89/391 EEC (framework directive), 89/654 EEC (workplaces), 89/655 EEC (work equipment), 89/656 EEC (Personal Protective Equipment), 90/269 EEC (manual handling of loads) and 90/270 EEC (display screen equipment)).
This Communication stated that there was evidence of the positive influence of EU legislation on national standards for occupational safety and health made up of both national implementing legislation and practical application in enterprises and public sector institutions.
In general, the report concluded that EU legislation had contributed to instilling a culture of prevention throughout the European Union as well as to rationalizing and simplifying national legislative systems. At the same time, however, the report highlighted various flaws in the application of the legislation that were holding back achievement of its full potential. It also noted cases where infringement proceedings had been opened.
REACH DNELS vs OELs
The European Union (EU) REACH legislation requires Derived No-Effect Levels (DNELs) to be calculated for substances produced in quantities above 10 tonnes/year. Meanwhile, the setting of occupational exposure limits (OELs) continues both at the member state and the EU levels. According to REACH, indicative OEL values (IOELVs) from the Commission may under some circumstances be used as worker-DNELs. On the other hand, worker-DNELs will be derived for several thousand substances, far more than the approximately 100 substances for which IOELVs have been established.
Thus, the procedure to set health-based OELs may become influential on that of DNELs and vice versa. It is observed in some studies that the REACH safety margins were approximately six times higher than those derived from the SCOEL documentation but varied widely with REACH/SCOEL safety margin ratios ranging by two orders of magnitude, from 0.3 to 58. Additionally, the REACH guidance document, although encompassing detailed advice on many issues, including default assessment factors for species and route extrapolation, gives little quantitative guidance on when and how to depart from defaults. At the end, a work of harmonization between the two systems is still needed to avoid misunderstanding about the procedure and/or different interpretations.
As said, the exposure to a chemical substance can be evaluated by calculating its related OEL (Occupational Exposure Level) by a quantitative approach or, in case of lack of toxicological data by assessing its OEB (Occupational Exposure Banding) by a qualitative approach.
As mentioned, in Europe we do not have a common Regulation or guidelines that regulates the method to carry out such a scientific work; it’s therefore useful to refer to other general regulations such as 1907/2006/EC (REACH) or some recommendation given by SCOEL (EU Scientific Committee of Occupational Exposure Level) or other non EU regulatory bodies such as US ACGIH. Additionally, a number of National Exposure Level have been set by national authorities in Europe and USA (please refer to figure n. 1). At European level we have a number of Directives setting OELs for a number of substances but not giving the assessment methods. Among these, we like to remember Directive 91/322 EEC, 2000/39 EC, 2006/15 EC, 2009/161 EU, 2017/164 EC and 2019/1831 EU (fifth list) EC giving a total number of 164 binding OELs for related substances. Few active pharmaceutical substances are included in the list as well as no pharmaceutical intermediates. If you like to know such values you can navigate into Gestis: International occupational exposure limit values for chemical agents edited by IFA (Germany).
Companies not having their manufactured substance in Gestis are obliged to calculate OEL or OEB on their own by adopting their own approach in a robust and scientific way. OEL/OEB assessment refers to the inhalation route of exposure as the most appropriate exposure route for workers. Adaptation may be necessary for other routes (dermal and oral).
Calculation of OEL by quantitative approach
The quantitative approach allows to have a numeric value of OEL (units/m3 of inhaled air). The NOAEL (NO Observed Adverse Effects Level) taken from animal toxicological studies is related to the body weight and to a number of uncertainty factors as per the following formula:
Where:
Weight adjustment = 60/70 Kg
F1: to consider the extrapolation between species
F2: 5 or 10 to consider variability between individuals
F3: 1 – 10 to consider the duration of toxicological studies
F4: 1 – 10 to evaluate the toxicity degree
F5: 1 – 10 to be applied on the basis of the toxicological dose used (NOEL, NOAEL,
LOEL, LOAEL)
α: Bioavailability
V: inhaled volume during 8 working hours. Usually = 10 m3
Bioavailability of the studied substance is crucial to assess the real exposure of the chemical into the body as it resulted in the so called “internal dose”.
Calculation of OEB by qualitative approach
When data on the substance are not directly available the qualitative approach is normally adopted. It allows to have an Occupational Exposure Band instead of a specific numerical number. The band is taken as reference for containment procedure during the manufacturing or use of the substance. The assignment of a specific band is given by the toxicologist on the basis of a weight of evidence approach assembling all available information on the substance including the pharmacological potency (h-API). The assessment may be corroborated/completed by the “in silico” evaluation (QSAR), if applicable, mainly for CMR effects (Carcinogenic, Mutagenic and Toxicity for Reproduction). Recently some “in silico” approaches have been set up also for sensitization and endocrine disrupting properties as well. Many band tables are available to assess the banding approach. Among these the Naumann’s table is one of the most used. Five Occupational Bands are described or 6 in the modified version. The Naumann’s table is often used for pharmaceuticals OEB approaches.
CONCLUSION
The assessment of worker exposure by assessing OEL or OEB is more and more a company activity as many OEL/OEB are not established by regulatory body at EU and/or US level. Therefore, it is strongly suggested to set a proper company policy for such an evaluation and stay coherent with the principle of this adopted policy.
