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

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

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

““Guidelines” Guidelines”

for for biological biological

monitoring – monitoring –

The BEIsThe BEIs®®

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.

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.

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.

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®

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

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

• 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

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

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

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

The The DocumentationDocumentation – – contentscontents

• Basis of the BEI®

• Uses and properties • Absorption• Elimination• Metabolic pathways & biochemical

interactions• Possible non-occupational exposure• Summary of toxicology

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

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

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)

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

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

Biomonitoring of benzeneBiomonitoring of benzene

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

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?

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?

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.”

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

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)

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

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

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

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?

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®?

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?

Other guidelinesOther guidelines

GermanyGermany

The The BATs BATs

from the from the DFGDFG

The HSE – The HSE – UK UK

Biological Biological monitoring monitoring guidelines guidelines

Guidance from WHO – Guidance from WHO –

How to do biological How to do biological monitoringmonitoring

Other Other

GuidelinesGuidelines

New edition, New edition, 20012001

Your questions pleaseYour questions please

Thank you for your attentionThank you for your attention

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