Biological Exposure Indices (BEIs ® ) Process and Use

1. Biological Exposure Indices (BEIs®)Process and Use Larry K. Lowry, Ph.D. Chair, ACGIH® BEI® Committee The University of Texas Health Center at Tyler

2. Where are we going today? • Current definitions of the BEI®, 2002 • The development of BEIs® • The key – Documentation • Examples • Biomonitoring without limits • Current and future issues • Resources

3. Biological monitoring. Why? • Assess exposure and uptake by all routes • TLV® not protective – skin • Includes workload • More closely related to systemic effects • Assess effectiveness of PPE • Legal or ethical drivers • Regulations • Control workers’ compensation costs

4. “Guidelines” for biological monitoring – The BEIs®

5. The BEIs® – 2003 BEIs® are intended for use in the practice of industrial hygiene as guidelines or recommendations to assist in the control of potential workplace health hazards and for no other use.

6. The BEI® – Definition • Biological monitoring … entails measurement of the concentration of a chemical determinant in the biological media of the exposed and is an indicator of the uptake of the substance. • The BEI® determinant can be the chemical itself; one or more metabolites; or a characteristic reversible biochemical change induced by the chemical.

7. BEIs® • Represent levels of determinants that are most likely to be observed in specimens collected from a healthy worker who has been exposed to chemicals to the same extent as a worker with inhalation exposure to the TLV®-TWA. • Generally indicate a concentration below which nearly all workers should not experience adverse health effects.

8. Current basis for BEIs® • Bio-equivalent to TLV® (traditional) • “BEIs® represent levels of determinants that are most likely to be observed in specimens collected from a healthy worker who has been exposed to chemicals to the same extent as a worker with inhalation exposure to the TLV®-TWA.” • Most of the BEIs® are based on TLVs®

9. Current basis • Indicators of early, reversible health effect • Approach developed in late 80’s as relationships did not always exist between airborne exposure and biomonitoring determinant. • Examples: • CO, Acetyl cholinesterase inhibiting pesticides, Cd, Pb, Hg, Hexane-MnBK

10. The BEI® CommitteeLarry Lowry, Ph.D., U TX Health Center at Tyler – Chair • Phil Edelman, MD, CDC – Vice Chair • Mike Morgan, Sc.D, CIH, U. of WA – Past Chair • Joe Saady, Ph.D., VA Division of Forensic Science • Leena Nylander-French, Ph.D, CIH, UNC, Chapel Hill • John Cocker, Ph.D., HSE, UK • K. H. Schaller, Dipl. Ing., Univ Erlangen, Germany • M. Ikeda, Ph.D., Kyoto Ind Health Assoc, Japan • Gary Spies, CIH, Pharmacia • Glenn Talaska, Ph.D., CIH, Univ of Cincinnati • Jan Yager, Ph.D., EPRI

11. BEI® development • Volunteer assigned document • Prepares draft Documentation • Sources of data • Human laboratory & workplace data • Limited use of animal data • Simulation modeling with verification • Published peer-reviewed data • Draft Documentation discussed in committee meetings, e-mail

12. Develop Select Review Assign BEI®? No Feasibility Chemical Data Author Yes Prepare Review Discuss Select Draft Draft Justification Determinant Return to Revise Yes Author No Final Document Development Process

13. How are chemicals selected? • Chemicals with human data • Potential for dermal absorption • Availability of adequate lab methods • Recommendations by others • Interest/experience of committee member

14. The Documentation • Who is the audience? • The practicing occupational hygienist or other practicing occupational health professional • What the Documentation is • Justification supporting the BEI® • Practical information on sampling, background, etc. • What the Documentation is not • An extensive review of toxicological data • A novel research approach to setting guidelines

15. The Documentation – contents • Basis of the BEI® • Uses and properties • Absorption • Elimination • Metabolic pathways & biochemical interactions • Possible non-occupational exposure • Summary of toxicology

16. For each index or BEI® • Analytical methods, sampling, and storage • Levels without occupational exposure • Kinetics • Factors affecting interpretation • Analytical procedures and sampling • Exposure • Population • Justification – the key • Current quality of database • Recommendations and references

17. The notations • B - Background levels expected • Nq- Nonquantitative • Biol. monitoring recommended, no BEI® • Ns- Non-Specific • Needs confirmation • Sq Semiquantitative (but specific) • Screening test • Confirmatory tests

18. Practical applications • Bioavailability of metals – Chromium • Chromium VI (water soluble) fume • Specificity and Sensitivity – Benzene biomonitoring • t,t-Muconic acid in urine (t,t-MA) • S-Phenylmercapturic acid in urine (SPMA)

19. Bioavailability of metals – Chromium • Physical properties and solubility • Cr (III), very insoluble particulates • Cr (VI) insoluble particulate – the lung carcinogen • Cr (VI) water soluble • Fume as generated in MMA arc welding • Mist as generated in electroplating • Health effects of Cr (VI) water soluble • Fume – lung irritant • Mist – chrome ulcers on skin, mucus membranes

20. Biological monitoring of Cr exposure • Cr (III) inappropriate – not bioavailable • Cr (VI) insoluble – not bioavailable • Cr (VI) water soluble • If fume, use BEI® based on welding studies • If mist, bioavailability less • See chrome ulcers at “acceptable” BEI® values

21. Biomonitoring of benzene

22. Biomonitoring at the current TLV® • t,t-Muconic acid in urine (t,t-MA) • Good sensitivity (to 0.1 ppm benzene) • HPLC methodology • Considerable variability in populations • S-Phenylmercapturic acid in urine (SPMA) • Ultimate sensitivity (to 0.01 ppm benzene) • GC/MS methodology • Good data base, but expensive

23. Biological monitoring without limits • What about substances absorbed through the skin and with chronic systemic health effects that occur after a long lag time such as cancer?

24. The traditional approach • Cannot relate to airborne limits, TLVs® • Irrelevant • Cannot relate to skin absorption • Difficult to quantitate dermal dose • Cannot relate to health effect • Often wrong timeline • What to do?

25. The BEI® approach • Rationale • Biological monitoring is essential to assess dermal exposure • How do you correlate dermal dose with a biomarker of exposure? • Nq Approach • “Biological monitoring should be considered for this compound based on the review; however, a specific BEI® could not be determined due to insufficient data.”

26. Criteria for an Nq • Dermal route of exposure significant • Good measurement methods • Good qualitative data on human exposure and biomarker concentration • Poor quantitative data relating exposure & biomarker • Long lag time, exposure to health outcome • Low or no background in general population

27. If criteria are met, then • Develop full Documentation • Describe sampling and analysis • Define background levels • Describe justification for biomonitoring • Note the lack of quantitative data • Cite guidance values from literature • Publish BEI® as Nq (no value)

28. Examples – MBOCA • Principal route of exposure – dermal • Alleged health effect in humans – cancer • Good methods and human data on exposure-response • Industry practice guidance from the HSE

29. Health and Safety Executive, UK • Scientific basis to justify guidance values • Use "yardstick or benchmark" approach • Issues • Results – no "safe" or "unsafe" exposure levels • Results – estimates of exposure areas and allow intervention to reduce exposures • No legal status • Examples – MBOCA and MDA

30. The “yardstick or benchmark” approach • Good analytical methods • All specimens analyzed by one laboratory or with a single method • Establish "best industry practice" using an upper 90% confidence limit of the "best" industries • Benchmarks – guidance value to provide users with assessment of their results

31. Current issues • Carcinogens? • Is there a safe level of exposure? • The German EKA approach • Mixtures and interactions • Metabolism/toxicokinetics on pure chemical • Workers exposed to mixtures • How does this effect BEI®? • Biomarkers of effect – irreversible effects? • Data gaps – lack of human data • Animal data – should this be used?

32. Skin absorption Justification for BEI® • Existing BEIs® for substances with substantial skin absorption • MBOCA – Nq • EGME/EGMEA – Nq • EGEE/EGEEA – 100 mg/g creatinine • (based on TLV® of 5 ppm) • Is this a valid approach? • Are Nq notations appropriate? • Should a chemical without a “skin” notation have a BEI®?

33. The future • As TLVs® drop, BEIs® based on TLVs® drop • Cannot distinguish exposure at TLV® from background • What do we do for substances that have no human data? • What is the future of modeling techniques? • Can these modeling techniques be validated? • Should animal data be used? • What about mixtures?

34. Other guidelines

35. GermanyThe BATs from the DFG

36. The HSE – UK Biological monitoring guidelines

37. Guidance from WHO – How to do biological monitoring

38. Other GuidelinesNew edition, 2001

39. Your questions please Thank you for your attention

40. Scheduled Break Take a minute to stretch!