Biological Exposure Indices
®
(BEIs )
Process and Use
Larry K. Lowry, Ph.D.
Chair, ACGIH® BEI® Committee
The University of Texas Health Center at Tyler
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
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
“Guidelines”
for
biological
monitoring –
®
The BEIs
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.
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.
®
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.
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®
®
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
®
The BEI Committee
Larry 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
®
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
Development Process
Select
Chemical
Review
Data
Assign
Author
Develop
Feasibility
BEI®?
Yes
Prepare
Draft
Review
Draft
Revise
No
Final
Document
Yes
Return to
Author
Discuss
Justification
Select
Determinant
No
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
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
The Documentation –
contents
•
•
•
•
•
Basis of the BEI®
Uses and properties
Absorption
Elimination
Metabolic pathways & biochemical
interactions
• Possible non-occupational exposure
• Summary of toxicology
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
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
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)
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
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
Biomonitoring of benzene
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
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?
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?
®
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.”
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
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)
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
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
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
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?
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®?
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?
Other guidelines
Germany
The
BATs
from the
DFG
The HSE –
UK
Biological
monitoring
guidelines
Guidance from WHO –
How to do biological
monitoring
Other
Guidelines
New edition,
2001
Thank you for your attention
Your questions please
Scheduled Break
Take a minute to stretch!