when the measured “dose” doesn’t make the poison smith_analytics exposure... · peter...
TRANSCRIPT
When the measured “dose”
doesn’t make the poison:
Some thoughts around analytics,
exposure science & toxicology
Ben Smith, Eric Chan & James Chan
A*STAR Innovations in Food & Chemical Safety (IFCS) Programme
“The opinions expressed in this presentation and on the following slides are those of the authors anddo not necessarily represent those of the Innovations in Food and Chemical Safety (IFCS) Programme,
A*STAR Research Entities nor any IFCS collaborators.”
Disclaimer #1My thoughts are my own!
I’m a Toxicologist by training, Risk Assessor by trade….analytical chemist by necessity!
Disclaimer #2Uncertainty/probability vs precision/accuracy
Artiste: Mark Heath (http://www.markheath.com)
Brief Introduction to A*STAR IFCS Programme
Exposure vs Dose
Chemophobia (“Drive to Zero”)
Understanding Exposure & Dose
– some IFCS activities
Regulatory Integration
Tripartite Collaboration
AgendaMore a collection of thoughts…
Dermal Toxicology
Mechanisms of Toxicity
Human organ models
Allergenicity
PBTK & Exposure Modelling
Focus Areas
A*STAR Innovations in Food and Chemical Safety (IFCS) ProgrammeEnhancing consumer safety through sound and sustainable science
Increase Singapore’s economic competiveness1
• Leverage Singapore’s scientific strengths to evolve
regulatory processes and develop relevant safety tools
• Grow Singapore’s branding for high quality and safe
food/consumer products
• Enhance the safety of Singaporean and global
consumers through sound and sustainable science
• Build expertise and grow future talent to stay ahead
of changing regulatory, industry and consumer trends
Protect Singapore’s population2
Food & Chemical Safety
Establish Singapore as the preferred hub in Asia
for companies to innovate & launch new products
Enable a proactive, science-driven and
harmonized regulatory environment
Why IFCS?Creating Growth, Enhancing Lives
Scientists & Regulators Industry
58.2% have
considered using
alternatives or
animal-free methods
57.7% feel that
non-animal
methodologies can
be established in
their field of research
Consumers
“What can I do for the environment?”
Industry needs to balance:
▪ Changing regulatory pressures
▪ Responsible use of natural resources
▪ Recognition social welfare issues
▪ Food/product safety requirements
▪ “Go-to-market” speed & ease“Humans are not 70kg mice”Thomas Hartung,CAAT, John Hopkins University
In Singapore...
Why IFCS?Changing trends across Singapore
“There are 100,000 chemicals in products we use every day and we are missing 90 per cent of the safety information we need”
Thomas Hartung, CAAT, John Hopkins University
A major challenge for society and industry
A global responsibility
Including AsiaTons of tainted melamine milk powder products have been destroyed in China in 2008 (Source: EPA)
Why IFCS?The cost of poor product safety
Etienne Thiry, Belgian Food Safety Agency
“Chemical hazards are largely present in the food chain. Their detection and quantification are of upmost importance. However, a real challenge is their huge diversity. It is essential to assist the risk manager with sound scientific opinions, especially for newly identified contaminants”
▪ 600 Mio people fall ill & 420K die from eating
contaminated food each year
▪ ca. US$ 95 billion in lost productivity & curtailed trade
annually (FAO)
Singapore Food Agency
• > 90% of Singapore’s food is imported
• Increasing novel food ingredient applications
Why IFCS?The complexity of the Singapore Food Story
✓ Are we asking the right questions about chemicals
in our environment (across the exposure to outcome
continuum)?
✓ Are we communicating properly about chemical
risks (what is the role of analytical chemists)?
✓ Are current analytical & toxicological tools being
utilised to best effect in supporting exposure, risk
assessment & safety research?
Session: Advance Food & Water Integrity Through Technology Innovation2019 Food and Water Summit: Fostering sustainability and integrity through collaboration
Analytical Chemists in the Wild West Toxicologists & PBTK Modelers in the Wild West
Exposure & DoseYou say pota(y)to, I say pota(a)to….
And the consumers say…Trace chemical safety and chemophobia
Melamine is toxic but…Trace chemical safety and chemophobia
A statement made by an instrument maker technical expert
at a technical meeting (not Waters!)
“Sensitive methods are requested by
regulators to analyze for highly toxic
contaminants like melamine.”
Melamine is not really “highly” toxic (acute oral LD50 in F344
rats is 3161 mg/kg body weight; NOAEL 8.4–10.9 mg/kg bw/day)
Issue is no one knew about it, sensitive sub-populations,
accumulative exposure…untargeted analysis issue
• US study found BPA concentrations in the urine of 2,157adults and children older than 6 years of age. 92% of thosesampled had BPA in their urine.
• Laboratory tests of the umbilical cord blood of 10 newbornsfound an average of 200 chemicals that can cause cancer,brain damage, birth defects and other health ailments,according to a study sponsored by the EnvironmentalWorking Group.
• A National Geographic writer chronicled his efforts to learnwhat chemicals were in his body. He was told that a fireretardant, PBDE, was found in his blood at levels 10 timesthe average found in a small study of US residents.
Biomonitoring reported in the press…Trace chemical safety and chemophobia
• All created fear/news stories, all commented on the sensitivity
of the analytical methods, none demonstrated that the
levels of chemicals detected posed any risk of harm.
Peter Sandman’s Formulae: (Perceived) Risk = 𝐻𝑎𝑧𝑎𝑟𝑑 (𝑂𝑢𝑡𝑟𝑎𝑔𝑒)
Safety / Risk
Assessments
Emotional
Response
David Galbraith, Cardno ChemRisk (2005)
Presentation to the International Society of Regulatory
Toxicology & Pharmacology
“Our vastly improved abilities to detect
have often outstripped our abilities to
detect meaning.”
Problems with data interpretationPutting exposure back into risk assessment
Communicating with granting bodies is a different matter!Using chemophobia for good!
So what are we doing to better understand exposure & dose?The IFCS road map: Looking across the exposure to outcome continuum
Inhalation
Ingestion
Dermal
So what are we doing to better understand exposure & dose?Current & developing areas under IFCS
Intake and Consumption HabitsConsumption surveys
Local exposure assessment case studies
Total Diet Study
(Bottom-up) Physiologically-based
ToxicokineticsTranslate external exposure to
internal tissue dosage
Singapore Branded FoodProducts
DatabaseData focus on Nutrition & Food Safety
(ingredients, packaging material, source)
BiomonitoringTargeted/untargeted analysis, body burden;
Link to exposure models
Model DevelopmentAggregate exposure for multi-use ingredients
Probabilistic Chemical Model®
Frequency Amount Substance Concentration
40g
Diary Day 1
500g
200g
90g
0.6%
0.02%
1.5%
0.007%
Material Concentration
20%
1%
5%
40%
Concentration data
Bornyl acetate
Food Chemical Intake & Probability of Addition/PresenceRefining the amount on the plate!
Daily
Average
Daily
Average
Daily
Average
Probabilistic Chemical Model®
PA= volume flavor material sold per food category/Total volume sold all flavors
X
X
X XX
1
0.51
10.2
0.2 0.5
1
0.80.7
XXX
XXXX X
0.5
Food Chemical Intake & Probability of Addition/PresenceRefining the amount on the plate!
Results
Benzaldehyde
Lower Higher
MeanMedian Consumer Exposure95th Percentile
Consumer Exposure
Population Exposure
Results
Benzaldehyde
Aggregate Exposure (fragrances)Multiple sources, concentrations, routes & even application sites
Raw Food AmountBioavailability
CorrectionChemical
Concentration
Actual Intake
*
Recipe Fraction Correction
*
Edible Portion Correction
*
Raw Product Correction
Correction Factor
Assay Concentration
*
Processing Correction
*
Limit of Reporting
Correction
Presence Probability
Chemical Intake =
× ×
∑ What you eat What’s in the food
How much you absorb× ×
Tissue
Dose
Correction Factor
×
How much reaches the
target×
Physiological Based Toxicokinetic ModellingExternal Exposure to Internal Dose
Systems data:
Human physiology
Metabolism Fraction
unbound
Transporters
Blood/plasma
ratio
PermeabilityLog P, Log D,
pKa
Chemical data:
In vitro ADME assaysPredicted
Toxicokinetics
+ =
Concept: Assemble multiple pieces of in vitro
data pertaining to ADME processes to predict
toxicokinetic profiles
Case study on 3 statins. Between 8-15
sets of in vitro data were used to build
PBTK models for each compound
Bottom-up PBTK ModellingAdopting a systems biology approach
KidneyIntestine Liver
J Pharm Sci. 2016 Feb;105(2):443-459
Acta Pharm Sin B. 2016 Sep; 6(5): 363–373
http://transportal.compbio.ucsf.edu/organs/small-intestine/
Metabolism/
ExcretionAbsorption Excretion
Statins as a first model for transportersUnderstanding the role of active transport in “chemical” uptake
Quantitative proteomics to measure transporter
and metabolic enzyme abundance – scaling factors
Transporter Cultured hepatocyte Liver tissue Whole liver
pmol/min/106
hepatocytes
Inter-cell type
difference
Down-regulation
in culturepmol/min/mg
total cell proteinMembrane vs
Whole cell
pmol/min/g liver pmol/min
Liver weight
Statins as a first model for transportersScaling factors for in vitro-to-in vivo extrapolation for transporters
Chem. Commun., 2016, 52, 8918-8934
(& modellers)
Building such models does requires chemical specific methods! Chemistry is the central science…
Parameter(units)
Clinical data
No scaling (Fold-difference)
With scaling (Fold-difference)
Cmax (ng/mL)37.10
177.96(4.80)
47.56(1.28)
AUC (ng/mL.h)
164.00 1695.49 (10.34)236.31(1.44)
CL(L/h)
48.904.72
(0.097)33.85(0.69)
IV 8 mg,
4 h
infusion
Rosuvastatin The importance of understanding physiological processes
PET imaging of [11C] labelled Rosuvastatin in humans
Clin Pharmacol Ther. 2019 May 18 (epub ahead of print)
Rosuvastatin liver concentrations
Interplay between
liver uptake,
metabolism,
efflux, excretion
Rosuvastatin Validation of predicted tissue concentrations
Ki = 1.11 ng/mLIC50 = 2.60 ng/mL
Rosuvastatin Inhibition of HMG-CoA Reductase
Ki = 1.11 ng/mL
Duration of action
Simulated Rosuvastatin Plasma and
Liver Concentrations
Time dimension – cellular recovery? Irreversible cellular injury?
Rosuvastatin The time makes the poison!
• Poly- and perfluoroalkyl substances (most widely studied arePFOA & PFOS)
• Found ubiquitously in humans (99% of blood samples)
• Exposure routes include consumer products, food, contaminatedwater sources
• Metabolically inert
• Biologically persistent with long half-lives (between 3.5-7.5 years)– why?
• Different routes of elimination (renal, biliary)
• Highly dependent on transporters
• Some SAR can be observed (chain length)
• PBPK models not sufficiently mechanistic, extrapolate from animaldata
• Vastly different animal and human disposition
PFOS, PFAS, PFOAAdvancing the Pace of Chemical Risk Assessment
In vitro to in vivo extrapolation (IVIVE) & reverse dosimetryHumans are not 70kg mice… but equally we are not 70kg culture plates!
Predict organ concentrations of chemicals to guide interpretation of in vitro toxicodynamic data
Reverse dosimetry
Scaling factor 1: microsomal protein per gram of liverIn vitro
CLuint
CLuint per g liver
Scaling factor 2: liver weight CLuint per
liver
WSM: liver blood flow, fraction unbound
CLH: Hepatic clearance
1. Break an in vivo process down (mechanistically) to a smaller, measurable unit
2. Design an in vitro assay to quantitatively measure that process
3. Scale the measurement (mechanistically) back to an in vivo process
Inter-individual variability Special populations Disease populations
Intra-species differences
“When CODEX started, toxicity and exposure data was primarily from the EU and US. This is not, especially for exposure, necessarily representative for Asia and other parts of the world. Although EU and US diets have been shown to be “similar”, Asian diets are very different and how Asians metabolize chemicals may be very different….we are now (in the panels & working groups) starting to see a lot more data coming from Asia and will keep seeing an increase in country specific data”
Dr. Yukiko Yamada (Japan); presented at CIFSQ, 7-8 Nov., Shanghai, China
Reducing testing, Reducing UncertaintyExtrapolation between species and sub-populations
Dede et al. Environ Toxicol Pharmacol. 2018 Jan; 57:104-114
PBTK as a complimentary tool for biomonitoringTiming makes the poison
Internal TTC Approach
Regulatory Toxicology and Pharmacology 103 (2019) 63–72
Regulatory Toxicology and Pharmacology 103 (2019) 63-72
The ultimate goalLinking PBTK to Toxicodynamic data & risk assessment approaches
Blaauboer et al. Considering new methodologies in strategies for safety assessment of foods and food
ingredients. FCT 91 (2016) 19-35
Integration into regulatory frameworksPartnering with the SFA on 21st century safety
Collaboration is the KeyA*STAR IFCS are keen to collaborate on case studies (across models) in this space
Future Ready Food Safety HubTripartite collaboration for Food Safety Leadership
Regulatory Readiness | Science & Innovation | Talent Development
✓ Building local food safety capabilities to support growing innovation in food production & manufacturing
✓ Developing the science for new food safety standards for industry and the region
Research is required to address gaps
in food safety capabilities and
technologies:
(i) Ascertain food safety of novel foods
and new food processing solutions
(ii) Develop intelligent supply chains
(iii) Understand consumer behaviour
towards food
(iv) Develop talent & training
Possible industry collaborators
But the question is how much are we actually exposed to? This is truly the ‘Golden’ age of exposure modelling supported by analytical chemistry!
Please check out the A*STAR IFCS Programme @ www.a-star.edu.sg/ifcs
Thanks – Any Questions?