Use of the RISK21 roadmap and matrix: human health risk assessment of the use of a pyrethroid in bed netting

Figures & data

Figure 1. The RISK21 roadmap.

Table 1. Doses of pseudomethrin absorbed as calculated for dipping and sleeping under the net in the first assessment.

Use		Dermal contact (mg/kg/d)	Hand to mouth (mg/kg/d)	Net mouthing (mg/kg/d)	Total or aggregate (mg/kg/d)
Net dipping (single exposure)	Adult	0.03–0.7	N/A	N/A	0.03–0.7
	Child	0.05–1.0	N/A	N/A	0.05–1.0
	Infant	N/A	N/A	N/A	N/A
	Sleeping under net (chronic exposure)	Adult	0.0002–0.16	N/A	N/A	0.0002–0.16
Child		0.0001–0.08	0.000002–0.006	N/A	0.0001–0.086
Infant		0.0005–0.4	0.000007–0.003	0.01–0.04	0.0106–0.443

Table 2. Key toxicological data for pyrethroids (values in mg/kg bodyweight).

	Chemical	Bifenthrin (FAO 2010)	Cyfluthrin (FAO 2003a)	Cypermethrin (FAO 2006)	Esfenvalerate (FAO 2002a)	Fenpropathrin (FAO 1993)	lambda-cyhalothrin (FAO 2003b)	Permethrin (FAO 1999)	Prallethrin (FAO 2002b)	Resmethrin (FAO 1996)	S-Bioallethrin (FAO 2005)
Rat	Acute LD50	53		160	90	71	79	225	490	8000	413
	Oral BMD20^a	14.3	12.6	76	40.5	29	8.9	156	150	291	135
	15–28-d NOAEL	10	20					50		36
	90-d NOAEL	3.8	9.5	40	7.5	17	2.5	60	79		20
	2-year – chronic NOAEL	2.3	6.2	7.5	2	5	2.3	25	19	3	27
	Mouse	15–28-d NOAEL		43			60		140
90-d NOAEL		45			10				374
2-year – chronic NOAEL		7.6	38.4	60	4	56	1.8	75	6	38	42
Dog		15–45-d NOAEL
	90-d NOAEL	2.5	6.5	12.5		7	0.5	5	3	80	42
	1-year NOAEL	1.5	6.5	5.7	5	3	0.5	5	2.5		14
	DART	Rat Dev Tox NOAEL Mat	1	3	17.5	2.5	3	10	225	10	200	20
Rat Dev Tox NOAEL Pup		2	30	70	20	10	15	225	300	200	80
Rabbit Dev Tox NOAEL Mat		2.7	20	450	3	6	10	200	30	240	50
Rabbit Dev Tox NOAEL Pup		8	20	700	20	36	30	1200	200	240	50
Rat Repro Parental NOAEL		3	9	3.8	4.2	3	2	170	36	4	60
Rat Repro Pup NOAEL		5	34.7	7.5	4.2	3	2	170	60	4	180
Reference NOAELs		Reference 1-d NOAEL	14.3	12.6	76	40.5	29	8.9	156	150	291	135
	Reference 90-d NOAEL	2.5	6.5	12.5	4.2	7	0.5	5	3	4	20
	Reference chronic NOAEL	1.5	6.5	7.5	2	3	0.5	5	2.5	3	14

a BMD20 values are from EPA (2011).

Figure 2. Application of the ranges for exposure and toxicity on the RISK21 matrix to form the exposure/toxicity intersect area for net dipping for the first assessment. The area to the left of the yellow shading indicates where exposure is below the human safe level for toxicity.

Figure 3. Application of the ranges for exposure and toxicity on the RISK21 matrix to form the exposure/toxicity intersect area for sleeping under the net for the first assessment. The area to the left of the yellow shading indicates where exposure is below the human safe level for toxicity.

Table 3. Doses of pseudomethrin absorbed calculated for dipping and sleeping under the net in the second assessment.

Use		Dermal contact (mg/kg/d)	Hand to mouth (mg/kg/d)	Net mouthing (mg/kg/d)	Total or aggregate (mg/kg/d)
Net dipping (single exposure)	Adult	0.028–0.04	N/A	N/A	0.028–0.04
	Child	0.04–0.06	N/A	N/A	0.04–0.06
	Infant	N/A	N/A	N/A	N/A
	Sleeping under net (chronic exposure)	Adult	1.6 × 10^−5–7x10^−5	N/A	N/A	1.6 × 10^−5–7 × 10^−5
Child		8 × 10^−6–4 × 10^−5	3 × 10^−6–9 × 10^−5	N/A	1.1 × 10^−5–1.3 × 10^−4
Infant		4 × 10^−5–2 × 10^−4	1.5 × 10^−5–4.5 × 10^−4	0.002–0.006	0.002–0.0067

Figure 4. Application of the ranges for exposure and toxicity on the RISK21 matrix to form the exposure/toxicity intersect area for net dipping for the second assessment. The area to the left of the yellow shading indicates where exposure is below the human safe level for toxicity.

Figure 5. Application of the ranges for exposure and toxicity onto the RISK21 matrix to form the exposure/toxicity intersect area for sleeping under the net for the second assessment. The area to the left of the yellow shading indicates where exposure is below the human safe level for toxicity.

Figure 6. Application of the ranges for exposure and toxicity on the RISK21 matrix to form the exposure/toxicity intersect area for net dipping for the third assessment. The area to the left of the yellow shading indicates where exposure is below the human safe level for toxicity.

Figure 7. Application of the ranges for exposure and toxicity onto the RISK21 matrix to form the exposure/toxicity intersect area for sleeping under the net for the third assessment. The area to the left of the yellow shading indicates where exposure is below the human safe level for toxicity.

Table 4. Comparison of effects for deltamethrin using full regulatory toxicology package and the studies “commissioned” using the RISK21 roadmap and matrix.

	Full regulatory studies package	RISK21 stepwise assessment
Lead effect	Neurotoxicity	Neurotoxicity
Other effects	None significant; from full package	None significant; from ToxCast assays
Short-term relevant NOAEL	1 mg/kg from dog study	1 mg/kg from dog study
Long-term relevant NOAEL	1 mg/kg from dog study	1 mg/kg from dog study
Number of animals used	2000+	24

Table 5. Summary of the assessments made using the RISK21 roadmap and matrix for dipping the net.

Assessment		Values used	Range
1. Tier 0	Exposure	Default values for dermal absorption in WHO generic model	0.03–1 mg/kg/d	Safety cannot be assuredRefine both exposure and toxicity
	Toxicity	Use BMD20 from most potent in series with default 100× with additional factor of 10×	0.0089–8.9 mg/kg/dAdult and child
	2. Tier 1	Exposure	Determine value for dermal absorption in human skin and use in WHO generic model		0.028–0.06 mg/kg/dAdult and child	Safety cannot be assuredRefine toxicity
Toxicity		Determine MEA IC50 as indicator of potency; estimate BMD50 value from MEA IC50. Apply default 100× and additional 3× for in vitro to in vivo	0.011–74 mg/kg/d
3. Tier 2		Exposure	As assessment 2	0.028–0.06 mg/kg/dAdult and child	Safety cannot be assuredRefine toxicity
	Toxicity	5-d dog study, neurological NOAEL with 100× extrapolation factor	0.01–1 mg/kg
	4. Tier 3	Exposure	As assessment 2, but derive kinetic profile for absorption to determine Cmax	0.028–0.06 mg/kg/dAdult and child		Study not done; therefore, conclusion not reached
Toxicity		Use kinetic values from 2-d dog study to derive Cmax for neurological effects and compare with exposure Cmax.	Proposed study

Table 6. Summary of the assessments made using the RISK21 roadmap and matrix for sleeping under the net.

Assessment		Values used	Range	Conclusion
1. Tier 0	Exposure	Default values for dermal absorption, net-to-skin transfer and net-to-saliva, and use in WHO generic model	0.01–0.4 mg/kg/dInfant	Safety cannot be assuredRefine both exposure and toxicity
	Toxicity	Use chronic NOAEL from most potent in series with default 100× with additional factor of 10	0.0005–0.5 mg/kg/d
	2. Tier 1	Exposure	Determine values for dermal absorption, net-to-skin transfer, and net-to-saliva, and use in WHO generic model		0.002–0.0067 mg/kg/dInfant	Safety cannot be assuredRefine toxicity
Toxicity		Determine MEA IC50 as indicator of potency. Apply default 100×	0.005–2.5 mg/kg/d
3. Tier 2		Exposure	As assessment 2	0.002–0.0067 mg/kg/dInfant	Safety can be assuredEnd assessment
	Toxicity	Five-day dog study, neurological NOAEL with 100× extrapolation factor, in vitro screens to exclude other toxicity	0.01–1 mg/kg/d

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