L22 Risk assessment human TH 2024.pdf

6/19/2024 L22 Human Risk Assessment Timo Hamers 1 Set-up  What is risk?  Comparison of risks by toxic compounds to other risk factors  How can critical exposures be determined? Compounds...

6/19/2024 L22 Human Risk Assessment Timo Hamers 1 Set-up  What is risk?  Comparison of risks by toxic compounds to other risk factors  How can critical exposures be determined? Compounds with and without a threshold value  Case-study Dioxins 2 1 2  6/19/2024 Paracelsus paradigm Paracelsus (1493-1541): „All Ding' sind Gift und nichts ohn' Gift; allein die Dosis macht, dass ein Ding kein Gift ist.“ 3 3 Risk = Hazard x Exposure 4 2 4  6/19/2024 Risk Assessment: part of Risk Management 5 5 Comparison of toxic risk to other risk factors  Toxic compounds versus overweight, traffic participation, etc  Express risks in terms of lost life years  Disability Adjusted Life Years (DALY) (for handicaps adjusted life years) 6 3 6  6/19/2024 Disability Adjusted Life Years (DALY)  DALY = YLL + YLD Years of Life Lost (YLL): years lost due to premature death Years Lost to Disability (YLD): years lived with disease  with YLL = n x standard life expectation in year of death YLD = n x handicap weight x duration disease till recovery or death  Example 1: Obese man gets diabetes type II at age of 27 and dies at age of 67 Life expectation: 75 years; diabetes has weight 0.2 DALY = 1x8 + 1x0.2x40 = 16 years  Example 2: 3000 people die in NL 10 years premature due to diabetes type II 1100000 people suffer from diabetes type II, with weight 0.2 Annual DALY loss in NL for diabetes = 3000x10 + 1100000x0.2 = 250000 years!!! (numbers are approximates) 7 7 Acrylamide  Industrial application Raw material for polyacrylamide Application in water treatment, oil drilling, sewage repair, PAGE, ….  Side product formed during heating of food “Cooking toxicants” Especially in starch-rich products at 180 ºC or higher 8 4 8  6/19/2024 Acrylamide Dearfield et al., 1995 9 9 Acrylamide  Carcinogenic compound  100 persons die per year On average 5 years lost of expected lifetime On average 2 years ill (50% disabled) DALY = 100 x 5 + 100 x 0.5 x 2 = 600 years 10 5 10  6/19/2024 “Ons eten gemeten” - RIVM 11 11 “Ons eten gemeten” - RIVM  DALY per year Smoking: 350 000 Unhealthy food: 300 000 – 400 000 Food infections: 1000 – 4000 Toxic compounds < 1000 Traffic accidents: 69 000 12 6 12  6/19/2024 DALY for different risk factors in The Netherlands Subject YLL YLD Scale YLL or YLD Asbestos A # ? unknown or uncertain Pesticides in water 0 ? # Data available, but not as Soil quality incl groundwater A/B ? YLD Drones/RPAS ? ? 0 No Electromagnetic fields A ? A 0-10 Noise B/C E B 10-100 Endocrine disrupting compounds ? ? C 100-1000 Nuclear plants 0 0 D 1000-10000 Ionizing radiation C/D C E >10000 Air quality E E Microplastics ? ? Nanomaterials ? ? New biotechnology ? ? Olivine ? ? External safety (transport of chemicals) 0 0 Shale gas ? ? Chemical substances A/B D UV radiation D D Air traffic A # Water traffic B # Rail traffic B # RIVM, 2017. Road traffic D E Water quality C C Een scan van de veiligheid en kwaliteit Water safety 0 0 van onze leefomgeving Self-conducting cars ? ? 13 13 Set-up  What is risk?  Comparison of risks by toxic compounds to other risk factors  How can critical exposures be determined? Compounds with and without a threshold value  Case-study Dioxins 14 7 14  6/19/2024 Risk assessment of compounds 15 15 Risk = Hazard x Exposure  Hazard Intrinsic character of the compound Qualitative (Hazard identification) > E.g. this compound causes infertility Quantitative (Hazard characterization) > E.g. NOAEL, LOAEL, …  Exposure Quantitative measure for the presence of hazard Exposure assessment > E.g. dose (mg per kg bodyweight per day)  (Vulnerability)  Risk Probability that a negative effect will occur (risk characterization) 16 8 16  6/19/2024 Compounds with a threshold value 110 Criticism to NOEC/LOEC: 100 Equal to test concentration 90 Sensitive for # replicates Sensitive for variation in response 80 Depends on statistical test chosen 70 No confidence interval Most data points ignored Response Respons 60 NOEC often gives ~20% effect Poor testing – High NOEC!!! 50 40 30 Safe 20 Unsafe 10 0 0.001 0.01 0.1 1 10 NOAEL LOAEL Dosis of Dose Concentratie 17 17 Dose-response curve: backward use 110 To derive a critical effect dose (CED) 100 or benchmark dose (BMD) 90 at a critical effect size (CES) 80 70 Respons 60 50 40 30 Safe Unsafe 20 CES= 10 0 0.001 0.01 0.1 1 10 CED BMD Dosis of Concentratie 18 9 18  6/19/2024 BMDL CED BMDL BMD BMD  CES: Critical effect size 95% CI  CED: Critical effect dose  BMD: Benchmark dose  CI: confidence interval  BMDL: benchmark dose lower confidence bound 19 19 Terms used in risk assessment  NOAEL: No Observable Adverse Effect Level  LOAEL: Lowest Observable Adverse Effect Level  TDI: Tolerable Daily Intake  CES: Critical effect size  BMDL: benchmark dose lower confidence boun  UF: Uncertainty factor 20 10 20  6/19/2024 Tolerable daily intake (TDI)  TDI = NOAEL/UF or BMDL/UF  UF = uncertainty factors 1. Interspecies: from test animal to human > Rat, mouse, dog, guinea pig, … is not a human being! 2. Intraspecies: from average person to most sensitive person > Infants, elderly, pregnant women 3. Shortcomings within the dataset > E.g. From “unsafe” to safe values: LOAEL to NOAEL > E.g. From acute to chronic toxicity 21 21 Risk assessment of compounds in general Lowest observed adverse effect level (LOAEL) in test animals :2-10 No observed adverse effect level (NOAEL) in test animals :10 Safe dose (NOAEL) in average human :10 Safe dose for sensitive humans So: safe dose is 200-1000x lower than the lowest dose having negative effects in test animals 22 11 22  6/19/2024 Mutagenic compounds have no threshold value 23 23 Compounds without a threshold value: single hit 24 12 24  6/19/2024 Compounds without a threshold value: single hit 25 25 Compounds without a threshold value: single hit No threshold value!!! Maximum Permissible Risk Maximum Permissible Risk Level (MPRL) No uncertainty factors! TDI 26 13 26  6/19/2024 REACH requirements for human toxicity data  >1 t/yr Irritation and corrosion, sensitation, mutagenicity in vitro (bacteria), acute toxicity  >10 t/yr Mutagenicity in vitro (mammalian), acute toxicity (more route of exposure), repeated dose (28d), reproduction, toxicokinetics  >100 t/yr Mutagenicity in vivo (somatic and germ cells), subchronic (90d), developmental toxicity, two-generation study  >1000 t/yr Carcinogenicity study 27 27 Set-up  What is risk?  Comparison of risks by toxic compounds to other risk factors  How can critical exposures be determined? Compounds with and without a threshold value  Case-study Dioxins 28 14 28  6/19/2024 O Cl Cl TDI estimation for dioxin Cl O Cl  Not based on DOSE (pg per kg bw per day)  Instead based on BODY BURDEN (ng per kg bw)  Assuming steady state in a one compartment model 29 29 First order toxicokinetics in a one-compartment model a kQ Q Q: ng per kg dQ a: ng per kg per day  a – kQ k: per day dt 30 15 30  6/19/2024 Steady state conditions (dQ/dt = 0) Equilibrium body burden= a/k Initial slope = a dQ  a – kQ dt a Qt  (1- e-kt ) k 31 31 After exposure: exponential decay Halflife time (t½): dQ Time to excrete half of  – kQ the body burden dt Qt  0.5  Q0  Q0  ekt½ Qt  Q0  ekt 0.5  ekt½ kt½  ln(0.5) ln2 ln2 t½  k 32 16 32  6/19/2024 O Cl Cl TDI estimation for dioxin Cl O Cl  Steady state: Qeq = a/k a = k*Qeq = (ln2/t½)* Qeq = f*I absorption (a) = fraction (f) of intake (I) I = a/f = ((ln2/t½)* Qeq)/f Qeq  Assumptions: t½ = 7.5 years = 7.5*365 = 2738 d f=50%=0.5  Imin = ((0.693/2738)*28) / 0.5 = 0.014 ng per kg per day  Imax = ((0.693/(2738)*73)/0.5 = 0.037 ng per kg per day 33 33 O Cl Cl TDI estimation for dioxin Cl O Cl  LOAEL reproduction and development (rat and monkey): 28-73 ng per kg bw  Corresponding intake in humans: 14-37 pg per kg per day  Uncertainty factors interspecies: 1 (based on BODY BURDEN) intraspecies: 5 shortcomings dataset: 2  Total uncertainty factor: 1 x 5 x 2 = 10  TDI is 1-4 pg per kg per day 34 17 34  6/19/2024 Risk communication: Processed and red meat Lancet, 26 October 2015 Processed meat: carcinogenic to humans (Group 1) based on sufficient evidence in humans that the consumption of processed meat causes colorectal cancer Red meat: probably carcinogenic to humans (Group 2A) based on limited evidence that the consumption of red meat causes cancer in humans and strong mechanistic evidence supporting a carcinogenic effect https://www.youtube.com/watch?v=RXRQNlxN5KY 35 35 Learning goals - After this lecture you  Understand the importance of Paracelsus paradigm in risk assessment  Understand the DALY approach to compare different types of risk  Understand how critical body burdens can be calculated into critical dose levels  Are able to make simple risk calculations: see WG04  Understand more complex risk calculations  Realize that risk assessment depends on the number, type and quality of assumptions and data fundamental choices made 36 18 36  6/19/2024 Please contact me if you want…  To do a literature study in the field of Human & Environmental Toxicology  To do an internship in the field of Human & Environmental Toxicology (see next slide)  To provide feedback on the digital text book of the course  [email protected] 37 37 Topics for internships/literature theses  Optimization of FITC-T4 purification and characterization using LC- MS/MS approaches Maria Margalef – [email protected]  Quantifying microplastics of the future in human matrix with pyrolysis- GC-MS Kas Houthuijs – [email protected]  Transformation products elucidation and identification using LC- MS/MS Ingrida Bagdonaite – [email protected]  Discrepancies in data found in databases and fundamental chemical identification concepts (Literature thesis) Ingrida Bagdonaite – [email protected]  Developing analytical methods for fluoropolymers in consumer products and environmental matrices (pyrolysis, GC-MS, F-NMR) Ike van der Veen – [email protected] 38 19 38