CHEMICAL HEALTH HAZARDS IN BREATHING GAS WHAT IS THE IMPACT OF EXPOSURE LIMITS

1. CHEMICAL HEALTH HAZARDS IN BREATHING GAS WHAT IS THE IMPACT OF EXPOSURE LIMITS Rune Djurhuus NUI AS

2. Occupational Exposure Limit = OEL Hyperbaric Exposure Limit = HEL • Tool to protect workers against adverse health effects from chemical exposure at the workplace • Knowledge of how the OELs are derived improves adequate application of the tool • OEL - 8 hrs workday onshore • HEL - continuous exposure for days for divers at pressure • Norway: HEL = OEL x 0.2 - primarily to compensate for increased exposure time

3. Occupational Exposure Limit = OEL • Process for establishing an OEL similar in many countries • Primarily evaluation of potential health effects • Varying impact of other factors - technical, economic • For medical drugs documentation is needed to demonstrate absence of adverse effects before marketing • For industrial chemicals documentation is needed to demonstrate presence of adverse effects before restrictions are imposed

4. Who establishes OELs ? • Authorities • Directorate of Labour Inspection, Norway • Petroleum Safety Authority Norway • Health and Safety Executive (HSE), UK • Occupational Safety and Health Administration (OSHA), USA • Organisations • American Conference of Governmental Industrial Hygienists (ACGIH), USA • American Industrial Hygiene Association (AIHA), USA • National Aeronautics and Space Administration (NASA), USA

5. Basis for OEL • Toxicological data • Studies of effects that chemicals have on living organisms including man, animals, experimental models with cells and microorganisms (in vitro systems) • Data are collected from the scientific literature

6. Human data • Epidemiological studies - interference from other chemicals, diets, lifestyle etc. • Experimental studies - low exposures of low toxic chemicals - effect observation - ethical conflicts ? • Intoxications - case studies • Accidents - atmospheric pollution - acute and long-term effects • Seveso, Italy, 1976, explosion and release of TCDD (dioxin) • Bhopal, India, 1984, explosion and release of methyl isocyanate

7. Animal data • Experimental studies - acute effects - from no toxic dose to fatal dose - effects on different organs • Long-term effects - CNS, heart/circulation, pulmonary effects, cancer • Animal studies may provide extensive information of toxic effects and mechanisms • Ethical conflicts - increased pressure to reduce the use of animal experiments

8. In vitro data • Isolated cells from animals and humans • Bacteria, yeast, algae • No ethical conflicts - may use large number of parallels to compensate for biological variation • Final toxic reaction often intracellularly in the body - the basal reaction is identical regardless if the cells are isolated in vitro or reside in the intact organism • May provide considerable information of mechanisms of action, but lacks the cooperative effect of different organs, distribution by blood stream etc.

9. LOAEL ? LOAEL NOAEL Dose-response/dose-effect curve LOAEL = Lowest Observed Adverse Effect Level NOAEL = No Observed Adverse Effect Level

10. Uncertainty factors • Chemical substance with limited toxicological data from rats • Long-term effects on several organs - dose-response curves indicate liver effect as critical • Inhalation 8 hrs - 7 days - 3 months - LOAEL = 400 ppm • UF10A = 10 - from rats to man • UF10H = 10 - variability in susceptibility • UF10L = 10 - from LOAEL til NOAEL. • UF = 10 x 10 x 10 = 1000 • OEL = 400/1000 ppm = 0.4 ppm

11. Availability of toxicological data variable • For some substances - considerable amount of data • Example - benzene - many studies both on experimental animals and cell cultures and epidemiological studies on humans • Others - lack of data - for some only few observations of single effects on animal species or cell culture, no human data • No. chemical substances > 32 millions (CAS, november 2007) • OELs for 700 - 1000 chemicals • Large number of substances with very few or no data regarding toxic effects

12. Trends in occupational exposure limits • Trend towards lower OELs due to increased knowledge: • Improved analytical methods • Adverse effects demonstrated at ever-lower levels • Example- OEL for benzene: • 1946: ACGIH, USA - 100 ppm • 1967: HSE, UK - 25 ppm • 1988: HSE, UK - 5 ppm • 1988: DAT, Noway - 1 ppm • 1990: Sweden - 0.5 ppm • 1997: ACGIH, USA - 0.5 ppm • 2003: HSE, UK - 1 ppm

13. Benzene • Bone marrow depression - suppresses development of cells in the bone marrow - carcinogenic - leukemia • Recent, large study of 250 workers at two shoe factories in China working with glue containing benzene • Significant reduction in most of the white blood cells after exposure to benzene levels below 1 ppm • Implies: Present OEL = 1 ppm may be too high to protect against adverse health effects of benzene Lan et al., 2004. Hematotoxicity in workers exposed to low levels of benzene. Science, 306 (December): 1774-1776. Kim et al., 2006. Modeling human metablism of benzene following occupational and environmental exposures. Cancer Epidemiol. Biomarkers Prev., 15: 2246-2252

14. Combination effects Detailed knowledge of metabolism and mechanisms of toxicants may reveal unexpected combination effects • Example: • Dichloromethane (DCM) - common solvent - has effects on CNS • DCM is metabolised in the body to CO • DCM affects both CNS and oxygen transport • Combination of DCM and CO at least additive effects at normobaric conditions • Probably similar combination effects at hyperbaric conditions ?

15. Chemical exposure in a hyperbaric system • Effect is a combination of at least 4 factors: • Chemical compound • High ambient pressure • Elevated oxygen level • Prolonged exposure for many days - no restitution period • Available scientific data: • Considerable knowledge of the effect of a number of chemicals • Some knowledge of the effects of pressure per se • Considerable knowledge of the effect of oxygen per se • Very limited knowledge of the combination effects of chemical compounds, pressure and oxygen

16. Examples - available data from hyperbaric exposure • Elevated oxygen level - data indicate negative effects on lung - data from divers and subjects exposed to HBO • Both in vivo and in vitro data indicate toxic effects of high pO2 • In vitro study indicated that 50 kPa O2 increased cytotoxic effects of the solvent limonene on human lung cells • Human study from simulated dive indicated reduction of detoxification system in blood cells - divers more susceptible to adverse effects of chemical contamination ? • When data is limited it is important to take into account those few that do exist !

17. OELs/HELs as protective tools are affected by • Aavailable knowledge and uncertainty in establishing OEL/HEL • Impact of other considerations than health - technical, economical, feasibility, utilsation value of chemical • Effect- threshold may not exist • Individual response varies - may find one or more individuals in a population that respond to the ever-lowest possible concentration • Ethical dilemma - some workers may not be protected by a OEL/HEL • Professional evaluations are subjective - conclusions may differ

18. OEL/HEL - no safe limit for adverse health effects • Risky to consider OEL/HEL as absolute borders for adverse health effects • Urgent need for more data - in particular concerning combination effects - and at hyperbaric conditions • The attitude of assuming that everything is OK as long as the working atmosphere is just below the actual OEL/HEL - may impede the continous effort to improve the working environment for divers

19. NUIs medarbeidere er helt på toppen Takk for oppmerksomheten !

20. Examples combination effects • Solvent: • Carbon tetrachloride (CCl4, solvent) + ethanol (EtOH) - fatty liver • CCl4 is metabolised to toxic metabolite by enzyme CYP2E1 • EtOH induces CYP2E1 - increases production of toxic metabolite • Increased toxic effect • Drug: • Acetaminophen (paracetamol, analgesic) + EtOH • Toxic metabolite formed by CYP2E1 - detoxified by GSH • EtOH induces CYP2E1 - increases production of toxic metabolite - exceeds detoxifying capacity - liver necrosis

21. Establishing hyperbaric exposure limits (HEL) - ideally • Collect all available data for each compound • Evaluate data with assumption of prolonged exposure up to 30 d • Consider available data on effect of elevated oxygen level on uptake, metabolism, elimination and toxicity • Consider available data on effect of high pressure on uptake, metabolism, elimination and toxicity • Determine critical effect - and the corresponding NOAEL • Evaluate the complete data set • Extrapolate data if necessary - use of uncertainty factors

22. For comparison - NASA - SMACs • NASA has established exposure limits for personnel in space • Spacecraft Maximum Allowable Concentrations (SMACs) • Spacecrafts/space stations are comparable to diving systems concerning "isolated room"-situation • Continous exposure 24 hrs a day for up to 180 days • Normal atmospheric oxygen content • Normal atmospheric pressure • NASA has issued SMACs for approximately 50 compounds - limits for 1-7-30-180 days of exposure • Process may be used as model for establishing HELs

23. Acquired knowledge - experimental studies • Hypothesis: • High oxygen level may increase toxic effects of chemical contamination • Example: Toxic effects of the solvent limonene increased by 50 kPa oxygen in human lung cells Rolseth et al., 2002. Toxicology, 170: 75-88.

24. Acquired knowledge - human studies • Both high oxygen level and pressure seem to affect cellular defence systems • Defence systems in blood cells reduced during saturation diving • Are divers more susceptible to adverse effects of chemical contamination ? Djurhuus et al., 2006. Aviat. Space Environ. Med., 77: 597-604.

25. Be prepared for lower HELs Reduce chemical contamination to lowest possible level!

26. Uncertainty in establishing OEL/HEL depends on • Available data and quality of data • Amount of data - more data probably reduce uncertainty • Systematic approach - current practice not always based upon systematic evaluation of all available data • Evaluations subjective - different professionals may reach different conclusions based upon same dataset

27. LD50 LOAEL ? LOAEL NOAEL Dose-response/dose-effect curve LD50 = Lethal Dose 50 % LOAEL = Lowest Observed Adverse Effect Level NOAEL = No Observed Adverse Effect Level