RISK21 Case Studies - NHRInehrc.nhri.org.tw/foodsafety/ref/(18)20151021.pdf · EXAMPLE #1: Simple...
Transcript of RISK21 Case Studies - NHRInehrc.nhri.org.tw/foodsafety/ref/(18)20151021.pdf · EXAMPLE #1: Simple...
RISK21 Case StudiesAnswer Key
EXAMPLE #1: Simple TTC Plot
CHEMICAL CRAMER CLASS EXPOSURE (ug/kg/d) EXPOSURE (mg/kg/d)
Chemical A III 10 1e-2
Chemical B III 0.2 2e-4
Chemical C SA 0.06 6e-5
Chemical D SA 0.00002 2e-8
Chemical E III 0.035 3.5e-5
Chemical F SA 0.00026 2.6e-7
Need to create 2 TTC plots based on the different Cramer Classes:
1) Cramer Class III (chemicals A, B, and E)2) Structural Alerts (chemicals C, D, and F)
Plots are in units of mg/kg/d – need to convert exposure units!
EXAMPLE #1: Simple TTC Plots
Chemicals B, E de-prioritized Chemicals D, F de-prioritized
EXAMPLE #2: Basic Risk Plot
CHEMICAL TOXICITY TOXICITY (mg/kg/d) EXPOSURE EXPOSURE (mg/kg/d)
Chemical A0.4 – 1.5 mg/kg/d 0.4 – 1.5
3.56 – 42 ppb (conc. in drinking
water)1e-5 - 1.2e-3
Chemical B 0.0067 – 0.123 mg/kg/d 0.0067 – 0.123 0.0007 – 0.053 mg/kg/d 0.0007 – 0.053
Chemical C 2.05 – 0.03 ug/kg/d 2.05e-3 – 3e-5 3.0 – 263 ug/kg/d 3e-3 – 0.263
Chemical D 529 – 2.65 mg/kg/d 0.032 – 7.6 0.032 – 0.09 mg/kg/d 0.032 – 0.09
• Need to make sure that units are consistent (like for like) (e.g., ug/kg/d or mg/kg/d)
• Need to calculate exposure estimates for the drinking water example (assuming 2L consumption and 70kg body weight)• .356 ppb = 356 ug/L = 3.56e-4 mg/L• (3.56e-4 mg/L * 2L consumption) / 70kg body weight
= 1e-5 Plots are in units of mg/kg/d – need to convert exposure units!
EXAMPLE #2: Basic Risk Plot
Initial Plot
MOE changed to 1:100
EXAMPLE #2: Basic Risk Plot
Point estimate for lowest toxicity value for Chemical D + 100x UF
Point estimate for lowest toxicity value for Chemical B + 1000x UF
EXAMPLE #2: Basic Risk Plot
• Would de-prioritize Chemical A and D• Might need to refine toxicity estimate for Chemical D• Refine exposure estimate for Chemical B• Refine exposure & toxicity estimate for Chemical C
EXAMPLE #3: FormaldehydeLocation Formaldehyde Air Concentration
Outdoor Ambient Environments
Unpopulated Areas 0.2 ppb (0.25 ug/m3)
Suburban Areas 2 – 6 ppb (2.5 – 7.5 ug/m3)
Heavily Populated or
Industrial Area
10 - 20 ppb
(12.3 – 25 ug/m3)
Indoor Ambient Environments
Office Building 7 - 13 ppb (16 ug/m3)
Manufactured
Homes
11 - 37 ppb (46 ug/m3)
Conventional
Housing
14 ppb (17 ug/m3)
Toxicity data range: 0.028 – 0.75 ppm (NOAEL values from chronic inhalation studies)
INDOOR EXPOSURE SCENARIO
OUTDOOR EXPOSURE SCENARIO
EXAMPLE #3: Formaldehyde
LOCATION EXPOSURE EXPOSURE (ppm) TOXICITY
Unpopulated areas 0.2 ppb 2e-4
0.028 – 0.75 ppmSuburban areas 2.0 – 6.0 ppb 2.0e-3 – 6.0e-3
Heavily populated or industrial area
10 – 20 ppb 0.01 – 0.02
LOCATION EXPOSURE EXPOSURE (ppm) TOXICITY
Office building 7.0 – 13 ppb 7.0e-3 – 0.013
0.028 – 0.75 ppmManufactured homes 11 – 37 ppb 0.011 – 0.037
Conventional housing 14 ppb 0.014
INDOOR
OUTDOOR
Exposure values converted to ppm
EXAMPLE #3: FormaldehydeOUTDOOR PLOT
INDOOR PLOT
EXAMPLE #3: Formaldehyde
EXAMPLE #4: Methoprene
ppm
(mg
methoprene/kg
corn)
µg methoprene/gram
corn
grams corn
eaten/kg body
weight /day
µg methoprene/kg
body weight/day
mg methoprene/kg
body weight/day
At MRL 5 54 20 0.02
1 5 0.005
At higher
detection0.5 0.5
4 2 0.002
1 0.5 0.0005
At lower
detection0.1 0.1
4 0.4 0.0004
1 0.1 0.0001
Toxicity data range = 50 – 250 mg/kg/d
90-day NOEL: 50 mg/kg-day in diet of rats or dogs
Chronic NOEL: 250 mg/kg-day in mice
Corn consumption (g/kg/d): ranges from 0.744 – 4.189 (~1 – 5)
Using CSFII Analysis and the methoprene concentrations in commodities…..
Exposure range = 0.0001 – 0.002
EXAMPLE #4: Methoprene
Application of 100x uncertainty factor to lowest toxicity value
EXAMPLE #5: In vitro (Part A)Toxicity value: BMD10 = 0.1 ug/LExposure values: 0 – 0.001 ug/L
Application of 100x UF on BMD10 – needed??
EXAMPLE #5: In vitro (Part B)
Use 2L per day water consumption to calculate total exposure
• Volume of distribution = 20L
• Amount of Chemical Z in body = 10 – 1000 ug/L * 2L consumption = 20 – 2000
ug/L
• Calculated exposure = 1 – 100 ug/L
IC10 value used for Toxicity estimate.
What is the assumption for uncertainty? Is 100x appropriate?
TOXICITYINFORMATION
EXPOSUREINFORMATION
CALCULATED EXPOSURE
Chemical Z 1 ug/L (Leydig cell assay)
10 – 1000 ppb in drinking water
1 – 100 ug/L
EXAMPLE #5: In vitro (Part B)
EXAMPLE #6: Fluoride
• Exposure scenario(s) of interest:• Exposure through drinking water, oral hygiene, & diet
• Population(s) of interest:• Children (due to highest potential exposure as well as risk of fluorosis)
• How to weigh beneficial(reduction in dental caries) versus negative effects (fluorosis)?
EXAMPLE #6: Fluoride
Source Concentration /
Content
Intake (mg/kg bw)a
Child Adult
Drinking waterb 0.7 - 1.2 mg/L 0.049 - 0.084 0.020 - 0.034
Dental hygiene 0.145 – 0.66 mg 0.007 - 0.033 0.0004 - 0.002
Diet 0.2 – 0.4 mg 0.010 – 0.02 0.003 - 0.006
Total intake 0.066 – 0.137 0.0234 – 0.042
TOXICITY INFORMATION
NOAEL of 0.06 mg/kg/day and a LOAEL of 0.12 mg/kg/day for the cosmetic effect of dental fluorosis in children
The minimum toxicity range for dental fluorosis is taken from a value of ≥2 mg/L (converted to 0.18 mg/kg/d based on child water consumption of 1.4 L/d and 15kg body weight) (MRC, 2002).
Evidence of skeletal fluorosis was seen at 0.56 mg/kg (child) and 0.23 mg/kg (adult).
EXPOSURE INFORMATION
EXAMPLE #6: Fluoride
• Low risk to adults• Moderate risk to
children for dental fluorosis at higher exposures
EXAMPLE #6: Fluoride
• Drinking water major source of exposure
EXAMPLE #6: Fluoride – Extra Credit
Level of protection from dental caries (conc. in DW) mg/kg body weight
No effect (<0.3 ppm) <0.021
Some effect (0.3 – 0.7 ppm) 0.021 – 0.049
Optimum effect (0.7 – 1.2 ppm) 0.049 – 0.084
EXAMPLE #6: Fluoride – Extra Credit
Estim
ate
of
effe
ct
(mg
/kg
/d)
EXAMPLE #7: Erythrosine (FD&C Red Dye No. 3)
• Determination of exposure via cherries:• Concentrations in cherries = 75 – 200 mg/kg
• Adult can eat up to 75 cherries per year * 5g per cherry = 375 g cherries / year (0.375 kg)
• Range• 0.375 * 75 = 28.125 mg red #3 / 70 kg adult = 0.4 mg/kg/year
• 0.375 * 200 = 75 mg red #3 / 70 kg adult = 1.1 mg/kg/year
• How much per day max? Estimate a conservative max consumption - ~10 cherries / day?• Range = 0.05 – 0.14 mg/kg/d
EXAMPLE #7: Erythrosine (FD&C Red Dye No. 3)
Red 3 Source Yearly exposure Daily Exposure
Cherries 0.4 – 1.1 mg/kg/yr 0.05 – 0.14 mg/kg/d*
Toothpaste Can you estimate? 7e-5 – 2e-4 mg/kg/d
Medicine Can you estimate? 1e-4 – 1.3e-2 mg/kg/d**
*Assuming 10 cherries / day maximum consumption**Assuming 10 pill / day maximum consumption
EXAMPLE #7: Erythrosine (FD&C Red Dye No. 3)
Red 3 Source
Daily Exposure Toxicity Information
Cherries 0.05 – 0.14 mg/kg/d LOAEL = 64 mg/kg/dNOAEL = 500 mg/kg/d (rat dvp)NOAEL = 251 mg/kg/d (thyroid follicular)Toothpaste 7e-5 – 2e-4 mg/kg/d
Medicine 1e-4 – 1.3e-2 mg/kg/d
TOTAL 0.05 – 0.153 mg/kg/d
Questions – what toxicity study do you use?What uncertainty factors do you apply? Why?
EXAMPLE #7: Erythrosine (FD&C Red Dye No. 3)
Raw data – no UFs applied 10X UF applied for LOAEL NOAEL10X UF applied for animal human10X UF applied for intra species variability
EXAMPLE #8: Chemicals in Drinking Water
CHEMICAL Solubility Exposure Based on Sol (mg/kg/d)Oxytetracycline 1000 28.57143
Acetaminophen 14000 400
Chlordane 0.01 0.000286
Styrene 310 8.857143
Toxaphene 5.50E-06 1.57E-07
Estradiol 3.6 0.102857
Heptachlor epoxide 0.05 0.001429
Picloram 430 12.28571
Atenolol 13300 380
Hexachlorobenzene 0.062 0.001771
Used assumptions of 2L water consumption / day and 70kg body weight
EXAMPLE #8: Chemicals in Drinking Water
Based on this analysis, chlordane and toxaphene would be eliminated from further analysis (de-prioritized)
EXAMPLE #8: Chemicals in Drinking Water
Plot measured exposure values against the TTC values
ng/L mg/L mg/kg/d
Oxytetracycline 4.70E+05 1.34E+04 1.34E-02
Acetaminophen 1.00E+05 2.86E+03 2.86E-03
Chlordane 1.00E+02 2.86E+00 2.86E-06
Styrene 4.60E+01 1.31E+00 1.31E-06
Toxaphene 1.40E+00 4.00E-02 4.00E-08
Estradiol 4.40E+01 1.26E+00 1.26E-06
Heptachlor epoxide 1.60E+04 4.57E+02 4.57E-04
Picloram 4.60E+05 1.31E+04 1.31E-02
Atenolol 1.20E+04 3.43E+02 3.43E-04
Hexachlorobenzene 3.03E+01 8.66E-01 8.66E-07
EXAMPLE #8: Chemicals in Drinking Water
Based on this analysis, HCB, and atenolol would be eliminated from further analysis (de-prioritized). Estradiol looks like it could also be, but is exempted from using the TTC because it is a steroid….so keep it in for additional analysis.
EXAMPLE #8: Chemicals in Drinking Water
EXAMPLE #9: New Antibacterial / Antifungal
1) What information do you need to determine how much can be safely added to toothpaste?• EXPOSURE
• Concentration in tooth paste (range, median, etc.)
• Estimated ingestion of toothpaste (per day, young – adult)
• TOXICITY• Acute toxicity (estimate)
• Chronic toxicity values [Reference Point/Point of Departure]
EXAMPLE #9: New Antibacterial / Antifungal
2) Calculation of children’s exposure range:
Data for the calculation:
(a) Body weight for child: 20 kg
(b) Toothpaste ingestion: up to 50% of 0.2 g = up to 0.1 g, twice a day = up to 0.2 g
(c) Concentration in toothpaste: 0.2-10%
ESTIMATED EXPOSURE
(b) x (c) /(a)
(0.2 g) x (0.002-0.1 g/g)/(20 kg) = 0.0004-0.02/20 = 0.00002-0.001 g/kg = 0.02-1 mg/kg bw/d
note: ingestion of toothpaste given as upper level only (50%)
EXAMPLE #9: New Antibacterial / Antifungal
3) Evaluation of maximum safe level based on toxicity information:SPECIES/STUDY NOAEL (ENDPOINT) (mg/kg) LOAEL (ENDPOINT) (mg/kg)
Mouse/90-d 25 (hematology/liver)
Mouse/18-mo 10 (hematology) 10 (liver)
Rat/4-d 7.23 (BMDL) (thyroid, T4)
Rat/90-d 100 (?)
Rat/2-yr 12 (hematology/spleen)
Hamster/90-d (?) 200 (Kidney, hematology?)
Hamster/95-wk 75 (?)
Baboons/1-yr 30 (?)
Relevant Reference Point: 10 mg/kg bw per day in the mouse or 12 mg/kg bw in the rat.
Rationale:
Liver effects considered not relevant Lowest values Covers the 30 mg/kg in baboons. Effects on thyroid hormones in rats not relevant for humans
EXAMPLE #9: New Antibacterial / Antifungal
Estimated maximum level in tooth paste:
Corresponding to exposure estimate up to 0.1 mg/kg
(0.0001 g/kg)
Concentration in toothpaste (x)
o (0.2) x (x)/20=0.0001
o (x)= (0.0001) x (20)/(0.2) = 0.002/0.2=0.01 g/g=1%
EXAMPLE #9: New Antibacterial / AntifungalProduct Type Adult intake (mg/kg/d) Child intake (mg/kg/d)
Oral products
Toothpaste 0.006 0.023
Mouthwash 0.004 -------
TOTAL ORAL 0.01 0.023
Dermal products (rinse off)
Liquid hand soap 0.001 0.005
Liquid body wash 0.005 0.006
Dishwashing detergent 0.003 -------
TOTAL DERMAL (rinse off) 0.009 0.011
Dermal products (leave on)
Body lotion 0.038 0.042
Facial moisturizer 0.005 -------
Deodorant 0.003 -------
TOTAL DERMAL (leave on) 0.046 0.042
CUMULATIVE* 0.065 0.076
* does not take into account % dermal absorption and duration of exposure
Note: the concentration in the various products not known.
EXAMPLE #9: New Antibacterial / Antifungal
if provided values represent mean or median
values cumulative exposure might be not
acceptable for a fraction of the population
refinements include:
o correction for % dermal absorption
(based on the plot this will provide
more refinement
o correction for duration of exposure
(based on the plot this will provide less
refinement)
o better estimate of ingestion of
toothpaste may also provide
refinement
EXAMPLE #9: New Antibacterial / Antifungal
Use and/or intake lower than estimated
Reregistration can be granted
Based on other considerations (e.g.:
efficacy), higher concentrations can be
allowed in products