A Framework for the development and application of biological monitoring guidance values Len Levy, Ruth Bevan, Greet Schoeters, Roel Smolders, Juergen Angerer, Ovnair Sepai, Kate Jones & John Cocker Institute of Environment and Health, Cranfield University, UK; Health and Safety Laboratory, UK; Health Protection Agency, UK; Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Ruhr University, Germany; Vito, Belgium.
From Hazard to Disease
BM: Requirements Ethics informed consent Why, what, when, how, meaning of results Matrix Blood, urine, saliva, breath etc Analyte Specific, metabolite, related to toxicity, stability, kinetics, dose-response Analytical Method Specific, accurate, precise,
Biological Guidance Values Health-based HBM 1 & 2 (HBM Commission) BEs (Summit Toxicology) BEIs (ACGIH) BATs (MAK/DFG) BLVs (SCOEL) BMGVs(HSE) Non-health-based Reference values BARs (MAK/DFG) BLWs (MAK/DFG) EKAs (MAK/DFG) Good OH practice (90% values) (HSE)
The need for a framework for BMGVs The problem: A need for more BM guidance values A need for more BM data A need to manage the journey from detection to understanding A need to understand the different BMGVs The solution? A framework describing utility and limitations of BM data & guidance values
Method Develop framework criteria Develop Framework Consult Advisory Group & Revise Test framework with model compounds Present Framework at a Workshop Revise & Publish
Expert Advisory Group
A Framework for BMGVs Level 1 Level 2 Level 3 Level 4 Data only Data & Toxicity Toxicity & interest based Probability based Either acceptable (eg clinical range) or unknown Do not exceed, try to reduce Safe level Safe level no adverse outcomes expected If unknown get data on toxicity & health outcomes Get data on sources and toxicology Get epidemiology data to check assumptions No further data needs
Framework Criteria 1 Level 1 Biomonitoring Data only (not health-based) available analytical method for the substance (or its metabolites) detection in a biological fluid (eg. blood and urine) data on toxicity of the substance or the meaning of results is not available. Utility very limited
Framework Criteria 2 Level 2 Biomonitoring data plus some interest (not health-based) Level 1 criteria and: good quality biomonitoring data some reason for concern regarding potential health effects based on hazard information some basic metabolism and toxicokinetic data insufficient data to propose a health-based BGV Examples: Reference Ranges, Control-based occupational BMGVs
Framework Criteria 3 Level 3 Toxicity Data (health-based) Level 2 criteria and: good quality biomonitoring data some reason for concern regarding health effects following exposure good metabolism and toxicokinetic data insufficient data to propose a epidemiology-based BGV. Examples: HBM 1 & 2, BEs, BATs, BEIs, BLVs
Framework Criteria 4 Level 4 Toxicity and probability data (health-based) Level 3 criteria and: good data from epidemiology studies
Testing the Framework Proforma Criteria uses, potential routes of exposure and current health concerns toxicity data, including biological effect monitoring data, if available selection of the most appropriate biomarkers, including information on reference ranges, occupational guidance value, PK or PBPK models, concentration of pure compound or metabolites in blood, urine, environment, inter- and intra-variability analytical methods, including detection limits, reliability, reference materials, external quality assurance, known confounders epidemiology data, including any data linking external exposure with health effect, data linking biological monitoring data with health effects identification of risk management procedures identification of susceptible groups and populations communication issues associated with different types of BGVs
Framework test compounds Level 1: Samarium Level 2 : Cypermethrin, Methyl tert-butyl ether, Platinum Polybrominated diphenyl ethers, TDI Level 3: Acrylamide, Di(2-ethylhexyl) Phthalate Toluene Level 4: Benzene Cadmium Lead
Level 1 data only, non-health based BGV Samarium Few data on toxicity and no published biological monitoring data Low acute toxicity of rare earth metals and samarium chelates used in cancer Occupational exposure to samarium may result in inhalation of dusts with possible development of pneumoconiosis Further work is needed to identify a reference range for samarium and its toxicokinetics
Level 2 non-health based upper limit value Platinum Identified as a potential health hazard due to its omnipresence in the environment. Major routes of uptake and population HBM reference ranges are known Well-validated sensitive analytical techniques available Very little known about associated health effects of exposure
Level 3 Toxicity based BGV Acrylamide Suspected carcinogen in humans Main sources of exposure are food and tobacco smoke Estimation of internal exposure carried out through measurement of the Hb-adduct of AA (AAVal) which reflects the AA dose taken up in the previous 4 months Reference ranges established for AAVal for adults and children Mercapturic acids of AA and GA are main metabolites, which are excreted with urine and represent exposure of the last two days.
Level 4 Toxicity and Probability Based BGV Cadmium Primary pathways for uptake, toxico- and pharmacokinetic properties, and associated health effects extensively validated Reference values and health based HBM-values documented Epidemiological studies have confirmed in vivo and in vitro findings on Cd exposure-dose-response continuum in the general population Analytical methods documented in internationally established standard operation procedures, reference materials available and confounders well known and accounted for Urinary Cd concentrations are an excellent biomarker to describe exposure to Cd and can directly be related to associated health effects.
Summary Table Test Chemical Framework Element Level Exposure: Toxicity: Biomarkers: Analytical: Epidemiology: Risk Groups: General Toxicokinetics Reference Detection Link between Management: Defined susceptible Population (inc half-life) ranges limits exposure and Exposure groups Susceptible Group(s) Dose-response relationship Occupational guidance Ref materials / QA scheme human health effect reduction measures Inter- and intraindividual variability Samarium Main metabolite(s) values PK / PBPK models Confounders Link between BM data and health effect 1 _ Platinum 2 Acrylamide 3 Cadmium 4
Conclusions The framework: Suggests 4 levels for different types of BMGV Levels are based on available data for hazard, exposure and risk Suggests minimum data requirements Helps to understand the different types of BMGVs and their limitations Helps with communication of BM results Helps to manage the journey
Next Steps Publish a peer-reviewed paper Make full report available on Cefic-LRI website Encourage other BM groups to test and refine this framework to fully assess utility Although not intended for regulatory purposes the framework might assist regulators who need to underpin their processes
Acknowledgements Members of the Advisory Group Holger Koch - for help with DEHP and workshop Funding by CEFIC LRI-HBM1-UCRA-0712