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!


Initial Plot

MOE changed to 1:100


Point estimate for lowest toxicity value for Chemical D + 100x UF

Point estimate for lowest toxicity value for Chemical B + 1000x UF


• 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)?


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


• Low risk to adults• Moderate risk to

children for dental fluorosis at higher exposures


• 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


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


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?


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


Based on this analysis, chlordane and toxaphene would be eliminated from further analysis (de-prioritized)


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


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 #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]


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%)


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


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.


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


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

RISK21 Case Studies - NHRInehrc.nhri.org.tw/foodsafety/ref/(18)20151021.pdf · EXAMPLE #1: Simple...

Documents

Transcript of RISK21 Case Studies - NHRInehrc.nhri.org.tw/foodsafety/ref/(18)20151021.pdf · EXAMPLE #1: Simple...