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Biological Exposure Indices Biological Exposure Indices (BEIs(BEIs®®))
Process and UseProcess and Use
Larry K. Lowry, Ph.D.Chair, ACGIH® BEI® Committee
The University of Texas Health Center at Tyler
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Where are we going Where are we going todaytoday??
• Current definitions of the BEI®, 2002• The development of BEIs® • The key – Documentation• Examples• Biomonitoring without limits• Current and future issues• Resources
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Biological monitoring. Biological monitoring.
Why?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
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““Guidelines” Guidelines”
for for biological biological
monitoring – monitoring –
The BEIsThe BEIs®®
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The BEIsThe BEIs®® – 2003 – 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.
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The BEIThe BEI®® – Definition – 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.
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BEIsBEIs®® • 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.
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Current basis for BEIsCurrent 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®
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Current basisCurrent 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
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The BEIThe BEI®® Committee Committee Larry Lowry, Ph.D., U TX Health Center at Larry Lowry, Ph.D., U TX Health Center at
Tyler – ChairTyler – 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
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• 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
BEIBEI®® development development
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Development Process
Select Chemical
Review Data
Assign Author
Select Determinant
Discuss Justification
Develop Feasibility
Prepare Draft
BEI®?
Review Draft
Return to Author
Revise
Final Document
Yes
No
No
Yes
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How are chemicals How are chemicals selected?selected?
• Chemicals with human data
• Potential for dermal absorption
• Availability of adequate lab methods
• Recommendations by others
• Interest/experience of committee member
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The The DocumentationDocumentation• 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
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The The DocumentationDocumentation – – contentscontents
• Basis of the BEI®
• Uses and properties • Absorption• Elimination• Metabolic pathways & biochemical
interactions• Possible non-occupational exposure• Summary of toxicology
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For each index For each index or BEIor 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
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The notationsThe 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
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Practical applicationsPractical 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)
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Bioavailability of Bioavailability of metals – Chromiummetals – 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
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Biological monitoring Biological monitoring of Cr exposureof 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
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Biomonitoring of benzeneBiomonitoring of benzene
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Biomonitoring at Biomonitoring at the current TLVthe 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
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Biological monitoring Biological monitoring without limitswithout limits
• What about substances absorbed through the skin and with chronic systemic health effects that occur after a long lag time such as cancer?
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The traditional The traditional approachapproach
• 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?
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The BEIThe BEI®® approach 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.”
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Criteria for an NCriteria for an Nqq
• 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
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If criteria are met, If criteria are met, thenthen
• 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)
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Examples – MBOCAExamples – 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
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Health and Safety Health and Safety Executive, UKExecutive, 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
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The “yardstick or The “yardstick or benchmark” approachbenchmark” 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
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Current issuesCurrent 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?
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Skin absorption Skin absorption Justification for Justification for
BEIBEI®®
– 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®?
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The futureThe 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?
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Other guidelinesOther guidelines
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GermanyGermany
The The BATs BATs
from the from the DFGDFG
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The HSE – The HSE – UK UK
Biological Biological monitoring monitoring guidelines guidelines
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Guidance from WHO – Guidance from WHO –
How to do biological How to do biological monitoringmonitoring
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Other Other
GuidelinesGuidelines
New edition, New edition, 20012001
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Your questions pleaseYour questions please
Thank you for your attentionThank you for your attention
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Scheduled BreakScheduled Break
Take a minute to stretch!