Presentation by Prof. George Gray, Director of the Centre for Risk Science and Public Health, George Washington University, at the Workshop on Risk Assessment in Regulatory Policy Analysis (RIA), Session 11, Mexico, 9-11 June 2014. Further information is available at http://www.oecd.org/gov/regulatory-policy/
Introduction to toxicology gases and metalsNITISH SHAH
For More Medicine Free PPT - http://playnever.blogspot.com/
For Health benefits and medicine videos Subscribe youtube channel - https://www.youtube.com/playlist?list=PLKg-H-sMh9G01zEg4YpndngXODW2bq92w
Presentation by Prof. George Gray, Director of the Centre for Risk Science and Public Health, George Washington University, at the Workshop on Risk Assessment in Regulatory Policy Analysis (RIA), Session 12, Mexico, 9-11 June 2014. Further information is available at http://www.oecd.org/gov/regulatory-policy/
Introduction to toxicology gases and metalsNITISH SHAH
For More Medicine Free PPT - http://playnever.blogspot.com/
For Health benefits and medicine videos Subscribe youtube channel - https://www.youtube.com/playlist?list=PLKg-H-sMh9G01zEg4YpndngXODW2bq92w
Presentation by Prof. George Gray, Director of the Centre for Risk Science and Public Health, George Washington University, at the Workshop on Risk Assessment in Regulatory Policy Analysis (RIA), Session 12, Mexico, 9-11 June 2014. Further information is available at http://www.oecd.org/gov/regulatory-policy/
Introduction to the adverse outcome pathways concept and framework, Catherine...OECD Environment
On 30 April 2019, the OECD organised a webinar on the Adverse Outcome Pathway (AOP) framework. The AOP framework is a collaborative tool that applies an innovative approach for collecting mechanistic knowledge from various sources that can eventually support chemical safety assessment.
The following questions were addressed:
What is the AOP framework and why should you care?
Why are we developing AOPs?
Why collaborations are encouraged and why should scientific societies be brought in?
What are the opportunities for collaboration in AOP development?
It will be an appropriate source for you to understand about the food toxicology. Further, the impacts of genetically modified are discussed in detail. the effects of toxicity in human and other living organisms are included in this document with examples.
INTRODUCTION
Toxicology is the science of the poisons. It also studies the nature, effects, detection, assessment and treatment of their effects on biological material.
Toxicology is a multidisciplinary science. The ultimate objective of the combined research is to determine how an organism is affected by exposure to an agent.
This includes an understanding of:
How the agent moves and interact with living cells and tissues of the organism;
What parts of the organism are affected by its presence and health outcomes of this exposure.
Evaluation of the toxicity of substances whose biological effects may not have been well characterized.
The influence of chemical toxicity is mainly
determined by the dosage, duration of exposure,
route of exposure, species, age, sex, and environment.
The goal of toxicology is to contribute to the
general knowledge and harmful actions of
chemical substances.
2. to study their mechanisms of action,
3. and to estimate their possible risks to humans
HISTORY
Dioscorides, a Greek physician in the court of the Roman emperor Nero, made the first attempt to classify plants according to their toxic and therapeutic effect. Poisonous plants and animals were recognized and their extracts used for hunting or in warfare.
In 1500 BC people used hemlock, opium, arrow poisons, and certain metals to poison enemies or for state executions.
Theophrastus Phillipus Auroleus Bombastus von Hohenheim (1493–1541) (also referred to as Paracelsus, a Roman physician from the first century) is considered "the father" of toxicology.
He stated that "All things are poisonous and nothing is without poison; only the dose makes a thing not poisonous.“
Mathieu Orfila (1813) is considered the modern father of toxicology.
In 1850, Jean Stas became the first person to successfully isolate plant poisons from human tissue.
Hippolyte Visart de Bocarmé used nicotine to kill his brother-in-law. He extracted nicotine from tobacco leaves.
The 20th and 21st Centuries have marked by great advancements in the level of understanding of toxicology. DNA and various biochemicals that maintain body functions have been discovered. Our level of knowledge of toxic effects on organs and cells has expanded to the molecular level.
Just providing the information on Impurities in drug substances & Drug products to share my view and the collected information from the web for knowledge purpose.
Occupational exposure limits (OEL) to chemical agents APIs - Quantitative Ris...Azierta
The Occupational Exposure Limit (OEL) is defined as the airborne concentration of a substance (expressed as a weighted average in time for a working day of 8 hours/day and 40 hours/working week) under which it is believed that nearly all workers may be repeatedly exposed (day after day, over a working lifetime) without adverse health effects (ACGIH, 2006; DFG, 2005).
Occupational exposure limits (OELs) are a useful tool to prevent adverse effects on health when managing chemical substances.
On a European scale…
• Employers are legally obliged to provide a work environment that does not threaten the health of the workers (Chemical Agent Directive 98/24/EC and Framework Directive 89/391/EEC).
• Under Directive 89/391/EEC, OELs can be developed nationally, Indicative Occupational Exposure Limit Values (IOELVs).
Introduction to the adverse outcome pathways concept and framework, Catherine...OECD Environment
On 30 April 2019, the OECD organised a webinar on the Adverse Outcome Pathway (AOP) framework. The AOP framework is a collaborative tool that applies an innovative approach for collecting mechanistic knowledge from various sources that can eventually support chemical safety assessment.
The following questions were addressed:
What is the AOP framework and why should you care?
Why are we developing AOPs?
Why collaborations are encouraged and why should scientific societies be brought in?
What are the opportunities for collaboration in AOP development?
It will be an appropriate source for you to understand about the food toxicology. Further, the impacts of genetically modified are discussed in detail. the effects of toxicity in human and other living organisms are included in this document with examples.
INTRODUCTION
Toxicology is the science of the poisons. It also studies the nature, effects, detection, assessment and treatment of their effects on biological material.
Toxicology is a multidisciplinary science. The ultimate objective of the combined research is to determine how an organism is affected by exposure to an agent.
This includes an understanding of:
How the agent moves and interact with living cells and tissues of the organism;
What parts of the organism are affected by its presence and health outcomes of this exposure.
Evaluation of the toxicity of substances whose biological effects may not have been well characterized.
The influence of chemical toxicity is mainly
determined by the dosage, duration of exposure,
route of exposure, species, age, sex, and environment.
The goal of toxicology is to contribute to the
general knowledge and harmful actions of
chemical substances.
2. to study their mechanisms of action,
3. and to estimate their possible risks to humans
HISTORY
Dioscorides, a Greek physician in the court of the Roman emperor Nero, made the first attempt to classify plants according to their toxic and therapeutic effect. Poisonous plants and animals were recognized and their extracts used for hunting or in warfare.
In 1500 BC people used hemlock, opium, arrow poisons, and certain metals to poison enemies or for state executions.
Theophrastus Phillipus Auroleus Bombastus von Hohenheim (1493–1541) (also referred to as Paracelsus, a Roman physician from the first century) is considered "the father" of toxicology.
He stated that "All things are poisonous and nothing is without poison; only the dose makes a thing not poisonous.“
Mathieu Orfila (1813) is considered the modern father of toxicology.
In 1850, Jean Stas became the first person to successfully isolate plant poisons from human tissue.
Hippolyte Visart de Bocarmé used nicotine to kill his brother-in-law. He extracted nicotine from tobacco leaves.
The 20th and 21st Centuries have marked by great advancements in the level of understanding of toxicology. DNA and various biochemicals that maintain body functions have been discovered. Our level of knowledge of toxic effects on organs and cells has expanded to the molecular level.
Just providing the information on Impurities in drug substances & Drug products to share my view and the collected information from the web for knowledge purpose.
Occupational exposure limits (OEL) to chemical agents APIs - Quantitative Ris...Azierta
The Occupational Exposure Limit (OEL) is defined as the airborne concentration of a substance (expressed as a weighted average in time for a working day of 8 hours/day and 40 hours/working week) under which it is believed that nearly all workers may be repeatedly exposed (day after day, over a working lifetime) without adverse health effects (ACGIH, 2006; DFG, 2005).
Occupational exposure limits (OELs) are a useful tool to prevent adverse effects on health when managing chemical substances.
On a European scale…
• Employers are legally obliged to provide a work environment that does not threaten the health of the workers (Chemical Agent Directive 98/24/EC and Framework Directive 89/391/EEC).
• Under Directive 89/391/EEC, OELs can be developed nationally, Indicative Occupational Exposure Limit Values (IOELVs).
Detection of Acrylamide & effect of pre-treatments on Acrylamide concentrati...Meesha Singh
Overview of Acrylamide, one of the most hazardous ingredients and a by- product present in potato chips.
Study of the effect of some pretreatments, viz. soaking in Calcium chloride and Citric acid on Acrylamide formation in potato chips.
Tentative procedure for the detection of Acrylamide via Soxhlet extraction.
Estimating the Maximum Safe Starting Dose for First-in-Human Clinical TrialsMaRS Discovery District
Part of the MaRS BioEntrepreneurship series session: Clinical Trials Strategy
Speaker: Beatrice Setnik
This is available as an audio presentation:
http://www.marsdd.com/bioent/feb12
Also view the event blog and summary:
http://blog.marsdd.com/2007/02/14/bioentrepreneurship-clinical-trial-strategies-its-never-too-soon/
Presentation by Prof. George Gray, Director of the Centre for Risk Science and Public Health, George Washington University, at the Workshop on Risk Assessment in Regulatory Policy Analysis (RIA), Session 9, Mexico, 9-11 June 2014. Further information is available at http://www.oecd.org/gov/regulatory-policy/
Presentation by Prof. George Gray, Director of the Centre for Risk Science and Public Health, George Washington University, at the Workshop on Risk Assessment in Regulatory Policy Analysis (RIA), Session 5, Mexico, 9-11 June 2014. Further information is available at http://www.oecd.org/gov/regulatory-policy/
Mey Akashah, "Risk Assessment and Improved Decision-Making," Harvard School of Public Health, Harvard Medical School, and Harvard Extension School, April 5 2012.
Course: Human Health and Global Environmental Change
BioVariance - Pediatric Pharmacogenomics in Drug DiscoveryJosef Scheiber
This slideset gives an overview of pharmacogenomic and pediatric dosing knowledge and various influence factors. Finally it shows an example on how to use this kind of Data within predictive approaches.
Summary of the OECD expert meeting: Construction Risk Management in Infrastru...OECD Governance
Presented at the OECD expert meeting "Construction Risk Management in Infrastructure Procurement: The Loss of Appetite for Fixed-Price Contracts", held on 17 May 2023 at the OECD, Paris and online.
Using AI led assurance to deliver projects on time and on budget - D. Amratia...OECD Governance
Presented at the OECD expert meeting "Construction Risk Management in Infrastructure Procurement: The Loss of Appetite for Fixed-Price Contracts", held on 17 May 2023 at the OECD, Paris and online.
ECI in Sweden - A. Kadefors, KTH Royal Institute of Technology, Stockholm (SE)OECD Governance
Presented at the OECD expert meeting "Construction Risk Management in Infrastructure Procurement: The Loss of Appetite for Fixed-Price Contracts", held on 17 May 2023 at the OECD, Paris and online.
Building Client Capability to Deliver Megaprojects - J. Denicol, professor at...OECD Governance
Presented at the OECD expert meeting "Construction Risk Management in Infrastructure Procurement: The Loss of Appetite for Fixed-Price Contracts", held on 17 May 2023 at the OECD, Paris and online.
Procurement strategy in major infrastructure: The AS-IS and STEPS - D. Makovš...OECD Governance
Presented at the OECD expert meeting "Construction Risk Management in Infrastructure Procurement: The Loss of Appetite for Fixed-Price Contracts", held on 17 May 2023 at the OECD, Paris and online.
Procurement of major infrastructure projects 2017-22 - B. Hasselgren, Senior ...OECD Governance
Presented at the OECD expert meeting "Construction Risk Management in Infrastructure Procurement: The Loss of Appetite for Fixed-Price Contracts", held on 17 May 2023 at the OECD, Paris and online.
ECI Dutch Experience - A. Chao, Partner, Bird&Bird & J. de Koning, Head of Co...OECD Governance
Presented at the OECD expert meeting "Construction Risk Management in Infrastructure Procurement: The Loss of Appetite for Fixed-Price Contracts", held on 17 May 2023 at the OECD, Paris and online.
ECI in Sweden - A. Kadefors, KTH Royal Institute of Technology, StockholmOECD Governance
Presented at the OECD expert meeting "Construction Risk Management in Infrastructure Procurement: The Loss of Appetite for Fixed-Price Contracts", held on 17 May 2023 at the OECD, Paris and online.
EPEC's perception of market developments - E. Farquharson, Principal Adviser,...OECD Governance
Presented at the OECD expert meeting "Construction Risk Management in Infrastructure Procurement: The Loss of Appetite for Fixed-Price Contracts", held on 17 May 2023 at the OECD, Paris and online.
Geographical scope of the lines in Design and Build - B.Dupuis, Executive Dir...OECD Governance
Presented at the OECD expert meeting "Construction Risk Management in Infrastructure Procurement: The Loss of Appetite for Fixed-Price Contracts", held on 17 May 2023 at the OECD, Paris and online.
Executive Agency of the Dutch Ministry of Infrastructure and Water Management...OECD Governance
Presented at the OECD expert meeting "Construction Risk Management in Infrastructure Procurement: The Loss of Appetite for Fixed-Price Contracts", held on 17 May 2023 at the OECD, Paris and online.
Presentation of OECD Government at a Glance 2023OECD Governance
Paris, 30 June, 2023
Presentation by Elsa Pilichowski, Director for Public Governance, OECD.
The 2023 edition of Government at a Glance provides a comprehensive overview of public governance and public administration practices in OECD Member and partner countries. It includes indicators on trust in public institutions and satisfaction with public services, as well as evidence on good governance practices in areas such as the policy cycle, budgeting, procurement, infrastructure planning and delivery, regulatory governance, digital government and open government data. Finally, it provides information on what resources public institutions use and how they are managed, including public finances, public employment, and human resources management. Government at a Glance allows for cross-country comparisons and helps identify trends, best practices, and areas for improvement in the public sector.
See: https://www.oecd.org/publication/government-at-a-glance/2023/
The Protection and Promotion of Civic Space: Strengthening Alignment with Int...OECD Governance
Infographics from the OECD report "The Protection and Promotion of Civic Space Strengthening Alignment with International Standards and Guidance".
See: https://www.oecd.org/gov/the-protection-and-promotion-of-civic-space-d234e975-en.htm
OECD Publication "Building Financial Resilience
to Climate Impacts. A Framework for Governments to manage the risks of Losses and Damages.
Governments are facing significant climate-related risks from the expected increase in frequency and intensity of cyclones, floods, fires, and other climate-related extreme events. The report Building Financial Resilience to Climate Impacts: A Framework for Governments to Manage the Risks of Losses and Damages provides a strategic framework to help governments, particularly those in emerging market and developing economies, strengthen their capacity to manage the financial implications of climate-related risks. Published in December 2022.
OECD presentation "Strengthening climate and environmental considerations in infrastructure and budget appraisal tools"
by Margaux Lelong and Ana Maria Ruiz during the 9th Meeting of the OECD Paris Collaborative on Green Budgeting held on 17 and 18 of April 2023 in Paris.
OECD presentation "Building Financial Resilience to Climate Impacts. A Framework to Manage the Risks of Losses and Damages" by Andrew Blazey, Stéphane Jacobzone and Titouan Chassagne. Presented during the 9th Meeting of the OECD Paris Collaborative on Green Budgeting held on 17 and 18 of April 2023 in Paris
OECD Presentation "Financial reporting, sustainability information and assurance" by Peter Welch during the 5th Session during the 9th Meeting of the OECD Paris Collaborative on Green Budgeting held on 17 and 18 of April 2023 in Paris
Presentation "Developments in sovereign green bond markets" by Ms. Fatos Koc during the 4th Session of 9th Meeting of the OECD Paris Collaborative on Green Budgeting held on 17 and 18 of April 2023 in Paris.
What is the point of small housing associations.pptxPaul Smith
Given the small scale of housing associations and their relative high cost per home what is the point of them and how do we justify their continued existance
ZGB - The Role of Generative AI in Government transformation.pdfSaeed Al Dhaheri
This keynote was presented during the the 7th edition of the UAE Hackathon 2024. It highlights the role of AI and Generative AI in addressing government transformation to achieve zero government bureaucracy
Jennifer Schaus and Associates hosts a complimentary webinar series on The FAR in 2024. Join the webinars on Wednesdays and Fridays at noon, eastern.
Recordings are on YouTube and the company website.
https://www.youtube.com/@jenniferschaus/videos
Many ways to support street children.pptxSERUDS INDIA
By raising awareness, providing support, advocating for change, and offering assistance to children in need, individuals can play a crucial role in improving the lives of street children and helping them realize their full potential
Donate Us
https://serudsindia.org/how-individuals-can-support-street-children-in-india/
#donatefororphan, #donateforhomelesschildren, #childeducation, #ngochildeducation, #donateforeducation, #donationforchildeducation, #sponsorforpoorchild, #sponsororphanage #sponsororphanchild, #donation, #education, #charity, #educationforchild, #seruds, #kurnool, #joyhome
Presentation by Jared Jageler, David Adler, Noelia Duchovny, and Evan Herrnstadt, analysts in CBO’s Microeconomic Studies and Health Analysis Divisions, at the Association of Environmental and Resource Economists Summer Conference.
Effects of Extreme Temperatures From Climate Change on the Medicare Populatio...
Modeling Dose Response for Risk Assessment, George Gray
1. Center for Risk Science and Public Health
Modeling Dose Response for
Risk Assessment
George Gray
Center for Risk Science and Public Health
Department of Environmental and Occupational Health
Milken Institute School of Public Health
2. Center for Risk Science and Public Health
The Dose-Response
Relationship
Toxicity is quantified through
the dose-response relationship
• Individual - change in severity of effect with dose
• Population - change in likelihood of response with dose
• different relationships for different effects
• shape of curve gives information about population
variability and toxicity of the compound
3. Center for Risk Science and Public Health
Individual Dose-Response
Function (Dose-Effect)
Example - Aspirin in humans!
Dose (mg/kg)
0! 100! 200! 300! 400! 500! 600!
death!
hemorrhage!
encephalophathy!
acidosis!
hyperventilation!
nausea!
therapeutic!
Severity
2004 US Data
• 21,000 reports to
poison control centers
• 43 deaths
4. Center for Risk Science and Public Health
Population Dose-Response
Function
• Made up of many individual dose-response
functions
• At each dose level, individual members of the
population either do, or don't, respond
• Measure proportion of population responding
at each dose level
5. Center for Risk Science and Public Health
Tolerance Distribution
Population of
Varying
Reserve
Capacity
There is a dose-response because higher doses exceed the
ability to tolerate the challenge in an increasing fraction of the population.
0 10 20 30 DOSE
%RESPONDING
40
0 %
100 %
6. Center for Risk Science and Public Health
The Population
Dose-Response Relationship
• For non-stochastic effects a dose response
relationship is the distribution of individual response
thresholds in a population
• The distribution of thresholds reflects variability in
sensitivity to the agent in the test population
• Variability is likely to differ by species/sex/strain
• Different modes of action or target sites may lead to
different dose-response relationships for different
adverse effects caused by the same agent in the
same species/sex/strain
7. Center for Risk Science and Public Health
Population Dose-Response
Function
Dose (mg/kg/day)
ProportionResponding
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 10 100
Liver Effects
CNS Effects
Lethality
Example - Aldrin in Rats!
8. Center for Risk Science and Public Health
Some Definitions
• NOAEL - No Observed Adverse Effect Level
the highest dose administered that does not produce
a statistically significant increase in an adverse
effect
• LOAEL - Lowest Observed Adverse Effect Level
the lowest dose tested which produces a
statistically significant increase in an adverse
effect
• Threshold
the dose level below which no adverse effects will
occur
9. Center for Risk Science and Public Health
NOAELs and LOAELs
Dose (mg/kg/day)!
0!
0.1!
0.2!
0.3!
0.4!
0.5!
0.6!
0.7!
0.8!
0.9!
1!
0! 1! 3! 10! 30! 100! 300! 1000!
NOAEL!
LOAEL!
Proportion Responding
Threshold!
10. Center for Risk Science and Public Health
What to Do?
• We have data from experiments with animals
• Often high doses
• Usually minimized interindividual variation
• Well controlled
• Want to say something about what might happen to
exposed humans
• Usually lower doses
• Presumably more – but unknown – variability
11. Center for Risk Science and Public Health
Dose-Response Assessment
in Risk Assessment
Two Primary Approaches
• Assume threshold for adverse effects
• Assume no threshold and proportional (linear)
relationship between dose and response
12. Center for Risk Science and Public Health
Two Approaches
• Long latency
• Irreversible, lesions become
independent of dose
• Caused by small, rare
events in a single cell
• Auto-amplifying, “all-or-
none”
• Generally treated as a non-
threshold process
• Often short latency
• Often reversible, lesions
may remain dependent on
dose
• Caused by collective effects
on many cells
• Severity depends on dose
• Generally treated as a
threshold process
Non-threshold Threshold
13. Center for Risk Science and Public Health
Tolerance Distribution
Population of
Varying
Reserve Capacity
There is a dose-response because higher doses exceed the
ability to tolerate the challenge in an increasing fraction of the population.
0 10 20 30 DOSE
%RESPONDING
40
0 %
100 %
14. Center for Risk Science and Public Health
Stochastic Events
There is a dose-response because, for all individuals, higher doses
cause a higher random chance of being “hit” (but only some actually are).
Population of
Uniform
Susceptibility
0 10 20 30 DOSE
%RESPONDING
40
0 %
100 %
Random Events
Increase with
Dose
15. Center for Risk Science and Public Health
The Goal of Noncancer Risk
Assessment
• The goal is identification of exposure levels that will be
below the population threshold - theoretically the
threshold of the most sensitive individual in a population
• Two Approaches
• Calculate risk value by adjusting data from animal
tests (or epidemiological studies) with uncertainty
factors
• Calculate margin of exposure (MOE)
16. Center for Risk Science and Public Health
Noncancer Risk Values
Sample definition - U.S. EPA Reference Dose (RfD)
An estimate (with uncertainty spanning perhaps an
order of magnitude) of a daily exposure to the human
population (including sensitive groups) that is likely
to be without appreciable risk of deleterious effects
during a lifetime
• Similar to WHO or CPSC Acceptable Daily Intake
(ADI), IPCS and JMPR Tolerable Intakes (TIs), etc.
17. Center for Risk Science and Public Health
Margin of Exposure
• Sample definition – Australian Department of Health and
Ageing
“The MOE provides a measure of the likelihood that a
particular adverse health effect will occur under the
conditions of exposure. As the MOE increases, the risk
of potential adverse effects decreases. In deciding
whether the MOE is of sufficient magnitude, expert
judgment is required. Such judgments are usually made
on a case-by-case basis and should take into account
uncertainties arising in the risk assessment process,
such as the completeness and quality of the database,
the nature and severity of effect(s) and intra/interspecies
variability”
18. Center for Risk Science and Public Health
Key Steps
• Identify available data
• Evaluate endpoints and dose-response relationships
• Choose “critical effect” in “critical study”
• Identify “point of departure” for critical effect
19. Center for Risk Science and Public Health
Effect or Adverse Effect?
• Matter of toxicological judgment - often depends on
how thoroughly a substance has been studied
examples
changes in body weight gain
increased liver enzyme levels
diarrhea or reduced stool size
fewer offspring
increased rates of malformed offspring
• Try to identify the “critical effect” in the “critical study”
• Identify NOAEL and LOAEL in critical study
20. Center for Risk Science and Public Health
Critical Study, Critical Effect?
Standard method is to choose the most sensitive sex of the the
most sensitive species for the most sensitive endpoint
Neurotoxicity
Hepatotoxicity
Mice
Rats
M
F
M
F
Mice
Rats
M
F
M
F
Dose (mg/kg)
NOAEL
21. Center for Risk Science and Public Health
Point of Departure
• Non-cancer risk estimates build from a “point of
departure” (POD) on the dose response curve of the
critical effect in the critical study
• Two primary approaches to setting POD
• NOAEL
• Benchmark dose
22. Center for Risk Science and Public Health
NOAEL as POD
Dose (mg/kg/day)!
0!
0.1!
0.2!
0.3!
0.4!
0.5!
0.6!
0.7!
0.8!
0.9!
1!
0! 2! 4! 8!
ProportionResponding
10!6!
NOAEL
LOAEL
23. Center for Risk Science and Public Health
Benchmark Dose Approach
• Begins with dose at “benchmark” level of response
instead of NOAEL
• Process:
• Identify critical effect and critical study
• Fit simple dose-response model with confidence
limits
• Identify dose at “benchmark” response (often
upper confidence limit on ED10)
• Apply appropriate uncertainty factors to
benchmark dose
24. Center for Risk Science and Public Health
Description of BMD
Dose!
Response
0.05
0.10
0.20
0.15
Dose-Response Fit to
Experimental Data
95% Confidence Limit
on Dose-Response
ED10 (BMD)BMDL10
25. Center for Risk Science and Public Health
Advantages of the BMD
Approach
• Provides consistent basis for calculating RfD or ADI
• Rewards bigger and better studies
• Includes information about shape of dose-response
relationship
• Provides information about risk at exposure near
benchmark dose
26. Center for Risk Science and Public Health
Concerns About BMD
Approach
• More laborious than NOAEL approach
• Some data sets may be difficult to model
• Choice of model may have strong influence on
BMD but no scientific criteria for choosing among
models
• Critical effect will still vary between chemicals
• BMD approach is more conservative than NOAELs
• NOAEL/BMD (1%,95%) ~ 30
• NOAEL/BMD (5%,95%) ~ 6
• NOAEL/BMD (10%,95%) ~ 3
27. Center for Risk Science and Public Health
Calculating Risk Values
• Point of Departure is adjusted by uncertainty factors
• Account for uncertainties and data amount/quality
• Uncertainty factors evolved as part of regulation and
have little empirical basis
• Factors differ depending on characteristics of the
critical study
28. Center for Risk Science and Public Health
Safety (Uncertainty) Factors
Extrapolation !Uncertainty Factor!
Animal to Human (H) ! !10!
Average to Sensitive Human (S) ! !10!
LOAEL to NOAEL (L) ! !10!
Less than Chronic to Chronic (C) ! !10!
Data Quality (MF) ! !1-10!
U.S. EPA Guidelines for Development of RfD*
*Barnes, D.G., and Dourson, M.L. (1988) Reference Dose (RfD):
Description and Use in Health Risk Assessments, Regulatory
Toxicology and Pharmacology 8:471-486
29. Center for Risk Science and Public Health
Animal to Human (10H)
• Adjustment for interspecies differences in sensitivity to
toxic agents
• Current justification based on observation that
animal’s metabolic rates scale approximately as
surface area (~BW2/3)
• This means that animals of higher body weight appear
more sensitive per mg/kg than smaller animals
• By this calculation a human is about 6 times more
sensitive than a rat, 4 times more sensitive than a
guinea pig, and 12 times more sensitive than a mouse
• Therefore factor of 10 is overestimate for some
species, underestimate of sensitivity differences for
others
30. Center for Risk Science and Public Health
Average to Sensitive Human
(10S)
• Adjustment to account for variability in response in
the human population
• Essentially says that most sensitive human may be
10 times more sensitive than average human (and
experimental animal)
• Empirical studies* of differences in sensitivity for
acute lethality in rats indicate that 92% of the time
range between most and least sensitive was less
than 10-fold (average difference was 2.4 fold)
* Dourson, M.L., and Stara, J.F. (1983) Regulatory History and Experimental Support of Uncertainty (Safety)
Factors, Regulatory Toxicology and Pharmacology 3:224-238
31. Center for Risk Science and Public Health
Less Than Chronic to Chronic
(10C)
• Since “safe exposures” like ADI or RfD are for
lifetime exposure it is preferred that NOAEL come
from chronic study
• If critical study and critical effect are determined to
be from less than lifetime exposure this factor is
used
• Empirical analysis of subchronic and chronic studies
in rats and dogs indicates that 96% of the time the
ratio chronic/subchronic NOAEL (or LOAEL) is less
than 10 with an average ratio of 2
32. Center for Risk Science and Public Health
LOAEL to NOAEL (10L)
• Sometimes the critical study finds an adverse
response at even the lowest dose tested meaning
that there is not a NOAEL, only a LOAEL
• When using LOAEL this factor of 10 is used
• An empirical analysis found all ratios of LOAEL to
NOAEL were less than 10 and 96% were less than 5
• Sometimes an adjustable factor between 1 and 10 is
used
33. Center for Risk Science and Public Health
Data Quality (MF 1-10)
• An additional factor used by the U.S. EPA to account
for data quality and quantity
• “The magnitude of the MF depends upon the
professional assessment of scientific uncertainties in
the study not explicitly treated [by other uncertainty
factors] e.g., the completeness of the overall
database and the number of species tested. The
default value for the MF is 1”
34. Center for Risk Science and Public Health
Calculate Risk Values
• Simply divide NOAEL (or LOAEL) of critical effect
from critical study by appropriate uncertainty factors
NOAEL!
UFH x UFS x UFL x UFC x MF!
= RfD (or ADI, TI etc.)!
35. Center for Risk Science and Public Health
Example
Example: Bromate!
Critical Effect – kidney hyperplasia!
Critical Study – male mice exposed for 100 weeks!
NOAEL – 1.1 mg/kg/day!
LOAEL – 6.1 mg/kg/day!
!RfD = 1.1 mg/kg/day!
! 10(H) x 10(S) x MF!
36. Center for Risk Science and Public Health
Example
Bromate (continued)
NOAEL – 1.1 mg/kg/day
RfD = 1.1 mg/kg/day
10(H) x 10(S) x 3 (MF)
RfD = 0.004 mg/kg/day
(0.000367 rounded off)
37. Center for Risk Science and Public Health
Different Choices
Non-Cancer Evaluation of PCBs (circa 2000)
Standard Level Critical Effect NOAEL Exposure Uncertainty
(Agency) (mg/kg/day) (mg/kg/day) Regimen Factors
RfD 0.00007 reduced 0.007 monkey 3H
(EPA) (70 ng/kg/day) birth weight exposed in diet 3S
for 22 months 3C
3 M
MRL 0.000005 decreased none monkey exposed 10H
(ATSDR) (5 ng/kg/day) immunoglobulin (LOAEL of by oil gavage 10S
levels after 0.005 7 days/wk for 10L
challenge mg/kg/day) 27 months
38. Center for Risk Science and Public Health
Using the Benchmark Dose
BMD!
UFH x UFS x UFC x MF!
= RfD (or ADI, TI etc.)!
39. Center for Risk Science and Public Health
The Margin of Exposure
(MOE)
_____RfV_____
Exposure
• Reference Value (RfV) is a point of departure (POD)
from toxicologic or epidemiologic data
• No Observed Adverse Effect Level
• Benchmark Dose (or bound)
• Exposure can be measured or modeled – reflect
variability
= MOE
40. Center for Risk Science and Public Health
Using MOE
MOE = PoD
Exposure
• Sufficiency of MOE is “matter of expert judgment”
• Usually MOE > 100 considered of minimal concern
• POD can be NOAEL or BMD - Organizations that use
MOE (Australia, EU, etc. rarely use BMD approach)
41. Center for Risk Science and Public Health
Advantages of RfV/MOE
Approach
• Faster – more chemical coverage
• More transparent – science policy choices made in
risk management phase
• Readily applied to different settings/uses (i.e., fit for
purpose (NAS and EPA))
42. Center for Risk Science and Public Health
Concerns About RfV/MOE
Approach
• How to calculate RfV?
• Which endpoints?
• sex/species/strain
• Concordance?
• How to judge adequacy of MOE (>100? >1000? >233?) –
are we putting science judgments in the wrong hands?
• Does use imply linearity (e.g., MOE of 500 is 5X better
than 100?
• Can it be used in benefit/cost analysis and other
important uses of risk assessment?
43. Center for Risk Science and Public Health
Non-Cancer Summary
• Noncancer risk assessment is predicated on the idea
of individual and population thresholds for adverse
effects
• The goal of non-cancer risk assessment is to
determine “safe” level of exposure for a population
• Current practice involves adjustment of NOAEL or
Benchmark Dose with uncertainty factors or
calculation of a margin of exposure (MOE)
44. Center for Risk Science and Public Health
Cancer Risk Assessment
• Sources of Data
• The extrapolation issue
• Current practice
45. Center for Risk Science and Public Health
Rodent Carcinogenesis
Bioassays
• Rats and mice
• Male and female
• 3 dose groups
• Control
• Maximum tolerated dose (MTD)
• MTD/2
• Exposure in feed, water, or by gavage
• 2 years
46. Center for Risk Science and Public Health
Low Dose Extrapolation
• Because the bioassay cannot directly detect the levels of
risk of interest, it is necessary to extrapolate.
• Many mathematical models have been proposed for low
dose extrapolation -- including the one-hit, the
multistage, the multi-hit and the Weibull.
• Although these models may give similar fits to the data in
the experimental region, they often give quite divergent
estimates of low dose risk.
• Some organizations choose not to model some
carcinogens and calculate MOE instead
47. Center for Risk Science and Public Health
Example – Saccharin
10-7 10-6 10-5 10-4 10-3 10-2 10-1 1 10
10-8
10-7
10-6
10-5
10-4
10-3
10-2
One Hit
Armitage-Doll
Weibull
Gamma Multi - Hit
Dose, d (ppm*)
AttributableRisk,P(d)–P(0)
Source: Taylor et al. Toxic Applied Pharmicol, 29, 154 Abstr. 200, 1974
48. Center for Risk Science and Public Health
Cancer Data Extrapolation
Assume “no threshold” and “linear”
Animal Toxicity Data
Response(ratiow/cancer)
Dose
mg/kg/day
10 20 30
0.1
0.4
1.0
0.9
0.8
0.7
0.6
0.5
0.3
0.2
0 40 50 60
10-7
10-8
0
0 10-6 10-5
Dose
mg/kg/day
CancerRisk
slope factor or
cancer slope factor
49. Center for Risk Science and Public Health
Current EPA Approach
• Model data in observed
range (essentially BMD)
• Assume low-dose linear
below observed
• Estimate Cancer Slope
Factor (CSF) from Point
of Departure (POD)
• CSF = 0.10/LED10
50. Center for Risk Science and Public Health
Differences in Potency
Pesticide Cancer Slope Factor
!(mg/kg/day)!
Linuron !1.5 x 10 !
Captan !4.7 x 10!
Acephate !3.7 x 10!
Cypermethrin !3.7 x 10!
Glyphosphate !2.7 x 10!
Fosetyl Al !3.3 x 10!
Azinphos-methyl !1.7 x 10!
-3!
-6!
-5!
-7!
-8!
-9!
-4!
-1!
51. Center for Risk Science and Public Health
Take Home Messages
• Risk assessment is the way toxicologic information is
processed to inform public health decisions
• For risk assessment, dose response relationships are
assumed to either have a threshold (primarily non-cancer
effects) or to be linear at low doses (primarily carcinogens
• The goal of non-cancer risk assessment is to determine
“safe” level of exposure for a population - current practice
involves adjustment of NOAEL or Benchmark Dose with
uncertainty factors
• Cancer risk assessment develops Cancer Slope Factors to
allow estimation of cancer risk associated with a specific
exposure – based on linear extrapolation of rodent bioassay
data