Bifenthrin Feb 2012

8/12/2019 Bifenthrin Feb 2012

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E Risk Sciences, LLP

March 2012

Environmental Exposuresand Potential Health

Effects of BifenthrinA Systematic ReviewKatherine von Stackelberg, ScD


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Systematic Review of Environmental Exposures and Potential Health Effects of Bifenthrin

Katherine von Stackelberg, ScDE Risk Sciences, LLP

Keywords:

Bifenthrin, weight-of-evidence, review, human health, synthetic pyrethroid, neurotoxicity,carcinogenicity


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Abstract: This paper explores the association between exposure to bifenthrin, a syntheticpyrethroid, and adverse human health outcomes through a systematic review of the literature.Bifenthrin is a known neurotoxicant to target organisms (e.g., insects) and the toxicological datashow the potential for acute effects in mammalian cell cultures, but only at the highest dosestested with no observable dose-response relationships and without cell death. There is no

evidence for carcinogenicity, either DNA-reactive or by some other mechanism. There are nodocumented reproductive or developmental effects in humans. Estimated equivalent in vivoexposures calculated from assay results in human cell cultures are significantly higher thanpredicted exposure estimates from regulatory agencies or observations. The availablebiomonitoring data are summarized, and a comparison of predicted exposure estimates fromregulatory risk assessments and potential effect levels from the literature are compared to showthat expected exposures are less than no adverse observed effect levels from toxicologicalstudies. Given the utility and efficacy of bifenthrin with respect to its termiticidal properties, theanalysis qualitatively suggests a net positive risk-benefit tradeoff.


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Table of ContentsAbstract ........................................................................................................................................... 3Introduction ..................................................................................................................................... 5Methods........................................................................................................................................... 6

Literature Search and Review ..................................................................................................... 6

Results ............................................................................................................................................. 7Pharmacokinetics ........................................................................................................................ 7

Oral Exposures ........................................................................................................................ 7Inhalation ................................................................................................................................ 9Dermal Absorption.................................................................................................................. 9Metabolism ............................................................................................................................. 9

Toxicity Studies .......................................................................................................................... 9Carcinogenicity ..................................................................................................................... 16Chronic Toxicity ................................................................................................................... 16Subclinical Effects ................................................................................................................ 18Regulatory Toxicity Values and Equivalent in vivoDoses Associated with in vitroEffects 24

Comparison of Toxicity Values to Predicted Exposures .............................................................. 25Conclusions ................................................................................................................................... 26References and Bibliography ........................................................................................................ 27


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Introduction

Bifenthrin is a synthetic pyrethroid insecticide with biochemical origins in the natural insecticidepyrethrum, an extract of the flower Chrysanthemum cinerariaefolium. It is used primarily as an

insecticide on turf, in homes, and for agricultural applications. Synthetic pyrethroids as a classare in the top ten for usage in the home and garden market (Grube et al. 2011), although havefallen in rank since 2004.

Synthetic pyrethroids are known neurotoxicants and that is their mode-of-action in targetorganisms. In mammals, the mechanism of action for neurotoxicity of pyrethroids results frominterference with the sodium gate in the nerve membrane by prolonging the open phase of thesodium channel gate when a nerve cell is excited (Soderlund et al. 2002; US EPA 2011).Synthetic pyrethroids are identified as Type I or Type II based on differences in basic structure(the presence or absence of a cyano group in the alpha position) and the overt symptoms of

poisoning at high doses in laboratory rodents. Type I pyrethroid acute toxicity is characterized byaggressive behavior, fine tremors, prostration, and high body temperature, referred to as Tsyndrome, while Type II acute toxicity is characterized by involuntary and irregular movements,choreoathetosis, and generally includes excessive salivation, referred to as CS syndrome(Breckenridge et al. 2009; Burr and Fry 2004).

Early published studies (as reported in Ray and Fry 2006) showed a toxicological picture for thesynthetic pyrethroids dominated by purely functional or pharmacological neurotoxicity(hyperexcitation) mediated by action on the voltage-gated sodium channel. Subsequent work

refined this picture by showing the additionalcontribution of actions upon other ion channels,

and the heterogeneity of sodium channel actions,but the pyrethroids remained primarily functionalneurotoxicants (Soderlund et al. 2002).Pyrethroids without an alpha-cyano groupgenerally show the weakest physiological effect(Wilks 2000). Type II commercial pesticides suchas deltamethrin and cypermethrin are generallymore acutely toxic than the type I pyrethroids suchas permethrin (Ray and Fry 2006). Figure 1shows the chemical structure of the primarybifenthrin isomer1 as well as the two primary

metabolites (discussed under pharmacokinetics).Bifenthrin is unique among the pyrethroids in thatit contains a non-cyano alcohol moiety and yet

demonstrates more of a CS-type acute intoxication (Soderlund et al. 2002). A study by Choi andSoderlund (2006) found that the activation and deactivation kinetics of bifenthrin clusteredclosely with those of the three established Type I compounds, suggesting a greater similaritywith Type I rather than Type II pyrethroids with respect to mechanism of action. Studies show

Figure 1: Structure of Bifenthrin 1(R)cis Acid Isomer

(I) and Metabolites (II and III)


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that acute effects of synthetic pyrethroids are reversible following acute exposures, and that thesecompounds cause limited cumulative toxicity, if any, following sustained exposure (Soderlund etal. 2002; US EPA 2011).

The US EPA recently completed a cumulative risk assessment for the synthetic pyrethroids (US

EPA 2011). Both the US EPA and the European Union have developed risk assessments forbifenthrin including predictions of short-term and long-term exposures (US EPA 2011; EC2010). In addition to a number in vivostudies in rodents and dogs submitted under variousregulatory programs, the results of 500 human cell culture assays are now available through theUS EPA ToxCast program (Wetmore et al. 2012) and the results for bifenthrin are presented inthis paper in the context of the other toxicological and exposure studies. This paper evaluates theweight-of-evidence for adverse effects in humans and explores the relationship betweenpredicted exposures and effect levels from the toxicological data.

Methods

Relevant citations are identified by conducting a search of the peer-reviewed literature fortoxicological and epidemiologic studies that have evaluated effects of exposure to bifenthrin.With respect to the toxicological studies, we evaluate the stated significance of observedresponses, the adequacy of study design and statistical analyses, the presence of dose responserelationships, the evidence for and against modes of action appropriate for environmentalexposures in the general public, and the consistency of outcomes within and across studies. Forthe epidemiological studies, we evaluate study design, how exposure was quantified and thepotential for exposure misclassification and what implications that might have for presentedconclusions, and the potential for concurrent exposures.

Literature Search and Review

The literature search included the following terms: effect* [and] bifenthrin (or) pyrethroid;pyrethroid [and] effect* [and] review. All major databases, search engines, and websites, wereused, including:

Citation Index/ISI Web of Science JSTOR National Library of Medicine/PUBMED/TOXNET Hazardous Substances DataBase (HSDB) MEDLINE (OvidSP) Google Scholar

Google Books TRIP database EMBASE (OvidSP) Scirus Environmental Research US EPA Office of Pesticide Programs Public Docket International Programme on Chemical Safety


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FAO Panel of Experts on Pesticide Residues in Food and the Environment and the WHOExpert Group on Pesticide Residues

Studies primarily focused on pharmacokinetics and pharmacodynamics are shown in Table 1.Table 2 presents the in vivoand in vitroanimal studies except for the ToxCast data, which are

shown in Table 3. Specific ToxCast assays were explored with respect to relevance of a mode ofaction, and for in vivoexposure levels at which in vitroeffects have been observed. Finally,predicted exposure levels from regulatory evaluations of bifenthrin are compared to thesetoxicological values.

Results

The literature search revealed numerous secondary sources for unpublished studies that, in mostcases, were submitted to regulatory agencies as part of pesticide evaluation and/or registration ineither the United States or Europe. As such, these studies were reviewed by expert panels, thesereviews were evaluated to ensure concordance (e.g., were the descriptions and key aspects of the

studies the same across the reviews). Table 1 summarizes the studies focused onpharmacokinetics of bifenthrin. Table 2 summarizes the toxicological studies except for theToxCast assay results, which are presented in Table 3.

Pharmacokinetics

Many of the studies identified in Table 1 were only available as summaries from the Joint Foodand Agriculture Organization (FAO) of the United Nations and the World Health Organization(WHO) Meeting on Pesticide Residues summary report on bifenthrin (JMPR 1992) which madereference to numerous unpublished pharmacokinetic and toxicological studies submitted toWHO in support of the peer-reviewed evaluation of the potential for adverse effects in humans.

These same studies were used by the US EPA Office of Pesticide Programs in their regulatoryreview of bifenthrin, and these form the basis of the pharmacokinetic summary presented here.

Oral Exposures

JMPR (1992) cites an unpublished study by El Naggar et al. (1983) in which rats were treatedwith a single oral dose of 5 mg/kg bw alcohol (phenyl)-14C-labelled bifenthrin. Approximately76%-79% of the administered radioactivity was eliminated via the feces and 6-7% via urinewithin the first 48 hours. Approximately 90% was recovered in excreta after seven days.Radiocarbon residues in most tissues were < 0.1 ppm, except for liver (up to 0.1 ppm), skin (upto 0.4 ppm) and fat (up to 1.7 ppm). A significant portion of the parent chemical was excreted

unchanged in the feces.

JMPR (1992) cites another unpublished study by El Naggar et al. (1991) in which the authorsinvestigated excretion of bifenthrin following oral administration of a single dose of 2.7 mg/kgbw to female or 5.2 mg/kg bw to male rats. Female rats averaged 30% excretion of radioactivityin bile, approximately 15% in the urine and the remaining 49% via feces. In male rats, theexcreted radioactivity averaged 19%, 11% and 25% of the 14C-dose in bile, urine and feces,respectively. In this case, over 90% of the excreted 14C-residue in the bile was in form of polar


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conjugates and less than 1% could be attributed to the parent compound. Total absorption via theoral pathway of bifenthrin using the sum of average biliary and urinary excretion and tissueconcentrations determined in the El Naggar et al. (1991) study yields a value of approximately50% in females and 36% in males, respectively.

The European Commission (EC 2010; EFSA 2009) use a value of 50% absorption via the oralpathway, while the US EPA assumes bifenthrin is 100% absorbed via oral exposures.

Organism Dose

Fraction

in Urine

Fraction in

Feces Metabolites Tissue Residues

Rat

5 mg/kg bw alcohol (phenyl)-14

C-

labelled bifenthrin 6%-7%

76%-79% in

48 hrs; 90% in

7 d Parent compound

Radiocarbon residues in most tissues

were < 0.1 ppm, except for liver (up to

0.1 ppm), skin (up to 0.4 ppm) and fat

(up to 1.7 ppm).

Rat

14C-bifenthrin in one of the following

dose regimens: control (vehicle only),

a single low-dose of 4 mg/kg bw,

multiple low-doses of 4 mg/kg

bw/day of non-radiolabelled test

material over a two-week period,

followed by a single radiolabelled

dose of 4 mg/kg bw or a single high-

dose of 35 mg/kg bw. 9%-15%

71%-84% in

36 hrs (low-

dose); 72 hrs

(high-dose) Parent compound

Fat 1 ppm; Most organs < 0.2 ppm (low-

dose); < 1ppm (high-dose)

Rat

acid- and alcohol-14

C-labelled

bifenthrin at single dose levels of 4

mg/kg bw or 35 mg/kg bw. Also

unlabelled bifenthrin for 14 days at 4

mg/kg bw/day followed by a single

low dose of radiolabelled bifenthrin.

66%-73%

(alcohol);

69-83%

(acid)

20-25%

(alcohol) and

13-22% (acid)

Fecal: hydroxylated parent

compound. Urinary: result of

hydrolytic and oxidative-hydrolytic

processes. Noticable increase in

metabolites in multiple low doses not measured

Rat

single oral low-dose of 5.4 mg/kg

bw; single oral high-dose of 36-43

mg/kg bw depending on sex; multiple

oral low-doses of 4.9 mg/kg bw. "majority"

Feces: hydroxylated parent

compound non-conjugates;

urinary: hydrolytic or oxidative

degradation in conjugate and non-

conjugate forms

Average peak concentrations of

radioactivity were 9.6 ppm in fat, 1.7

ppm in skin, 0.4 ppm in liver, 0.3 ppm in

kidney, 1.7 ppm in ovaries, 3.2 ppm in

sciatic nerve, 0.06 ppm in whole blood

and 0.06 ppm in plasma

Female rat

radiolabeled oral 0.5 mg/kg bw/d for

70 days NA NA

Parent chemical accounted for a

majority (65%-85%) of the 14C-

residues in fat; also three

metabolites.

Half-lives of 51 days (fat), 50 days

(skin), 19 days (liver), 28 days (kidney),

and 40 days (ovaries and sciatic nerve)

were estimated from14

C-depuration.

Lactating

goats

radiolabeled oral 2 mg/kg bw/day for

7 days. NA NA

14C-residues isolated as

organosoluble, non-conjugated

products. Also hydrolytic and

intact ester metabolites.

75%-82% of total14

C-residues (ca. 1

ppm). Fat contained 78%-80% (ca. 1.7ppm) parent compound, muscle 74%-

88% (ca. 6.2 ppm), heart 77% (ca. 0.4

ppm), kidney 16%-22% (0.1 ppm) and

liver 19%-44% (0.8 ppm)

Lactating

goats 2 mg/kg bw/day for 7 days 40%-52% 8%-17% None reported

liver (3.9 ppm), fat (2.8 ppm), kidneys

(1.0 ppm) and heart (0.6 ppm)

Long Evans

rat and

human

hepatic

microsomes

added 100% cis-bifenthrin in the

presence and absence of NADPH NA NA

Intrinsic clearance (measure of the

metabolic rate) of bifenthrin was 5-

to 15-fo ld greater in rat relative to

human and solely the result of

o xidative processes in bo th NA

See Table 3 for ToxCast assay results.

in vivo Studies

in vitro Studies

Table 1: Pharmacokinetic Studies


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Inhalation

Absorption via inhalation is assumed to be 100%, but inhalation exposures have generally beenshown to be very low as compared to dermal or oral, given the low vapor pressure of bifenthrin(US EPA 2011; EC 2010; JMPR 1992).

Dermal Absorption

An in vivostudy in rats showed that amount of bifenthrin eliminated in the urine and feces wasless than 1% of the dose applied, even after 24 hours exposure. The amount absorbed (includingthe amount in the skin) was 55.14% at 10 hours and 69.1% at 24 hours. A second in vivostudy inshaved rats dermally dosed with an aqueous emulsion showed that after a contact time of 24 h,19% of the dose was recovered on the skin and about 73% in the skin wash with radioactivity inthe residual carcass less than 2% (JMPR 1992; EFSA 2008). US EPA recently used a dermalabsorption factor of 5% based on uncited studies in their cumulative risk assessment of syntheticpyrethroids (US EPA 2011).

Metabolism

Soderlund et al. (2002) report that for workers exposed to allethrin and volunteers or workersexposed to permethrin, cypermethrin, cyfluthrin, or deltamethrin, the metabolites identified inurine samples were consistent with the metabolic pathways for these compounds identified inrodents. An in vitrostudy using rat and human hepatic microsomes found that in both cases, theprimary metabolic pathway was the result of oxidative processes, and the intrinsic clearance (ameasure of the metabolic rate) of bifenthrin was 5- to 15-fold greater in the rat relative to humanmicrosomes (Scollon et al. 2009). These authors note that the parent pyrethroid is generallybelieved to be the neurotoxic entity as metabolism tends to decreases potency (Scollon et al.

2009; Soderlund et al. 2002), although no formal studies of bifenthrin could be found to directlycorroborate this conclusion. The most significant metabolite of bifenthrin is 2-methyl-3-phenylbenzoic acid (MPA), the clearest indicator of bifenthrin exposure (Ciner et al. 2010; Smithet al. 2002).

Yang et al. (2009) found that bifenthrin weakly activated human pregnane X receptor (PXR) butefficaciously activated rat PXR, suggesting differences in metabolic rates and outcomes inhumans as compared to rodents that could have implications for potential toxicity.

US EPA ToxCast in vitroassay results (shown in Table 3) indicate that bifenthrin induced P450metabolic pathways at equivalent in vivoconcentrations greater than 0.12 mg/kg-d.

Toxicity Studies

Only one study was identified conducted in vivoin humans. A single, short-term epidemiologicstudy was developed by Srivistava et al. (2005) based on occupational users of bifenthrin. Tenhealthy males wearing protective gear sprayed 25 mg/m2of bifenthrin on interior walls six hoursdaily for five consecutive days. Clinical and biochemical tests were conducted prior to exposureand on days four and seven following exposure. Tests included lung function, hepatic function,


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Table 2: Toxicological Studies for Bifenthrin

Guideline/

Reference

Study Type MRID No. (year)/ Classification /Doses Results

870.3100 90-Day oral

toxicity (rat)

00141199 (1984) Acceptable/guideline

M: 0, 0.88, 3.8, 7.5, 15 mg/kg/day

F: 0, 1.04, 4.3, 8.5, 17.2 mg/kg/day

NOAEL = M/F: 3.8/4.3 mg/kg/day

LOAEL = M/F: 7.5/8.5 mg/kg/day based on increased

incidence of tremors.

870.3150 90-Day oral

toxicity (dog)

00141200 (1984) Acceptable/guideline 0, 2.21,

4.42, 8.84, 17.7 mg/kg/day

NOAEL = M/F: 2.21 mg/kg/day LOAEL = M/F: 4.42 mg/kg/day

based on increased incidence of tremors.

870.3200 21/28-Day

dermal toxicity

(rat)


0, 23, 47, 93, 932 mg/kg/day

NOAEL = 47 mg/kg-d

LOAEL = 93 mg/kg/day based on staggered gait and

exaggerated hindlimb flexion.

870.3200 21/28-Day

dermal toxicity

(rabbit)


0, 22, 44, 88 442 mg/kg/day

NOAEL = 88 mg/kg/day

LOAEL = 442 mg/kg/day based on loss of muscle coordination

and increased incidence of tremors.

870.3700a Prenatal

developmental in

rat (gavage)

00154482 (1983) Acceptable/non-guideline

0, 0.44, 0.88, 1.77, 2.2 mg/kg/day

Maternal NOAEL = 0.88 mg/kg/day LOAEL = 1.77 mg/kg/day

based on tremors during gestation.

Developmental NOAEL and LOAEL were not established

(fetuses were not examined).

870.3700a Prenatal

developmental in

rat (gavage)

00141201 (1984)

Acceptable/guideline

0, 0.44, 0.88, 1.77 mg/kg/day

Maternal NOAEL = 0.88 mg/kg/day LOAEL = 1.77 mg/kg/day

based on tremors. Developmental NOAEL = 0.88 mg/kg/day

LOAEL = 1.77 mg/kg/day based on increased fetal and litter

incidence of hydroureter without nephrosis.

870.3700a Prenatal

developmental inrat (diet)

45352301 (2001)

Acceptable/guideline0, 2.4, 4.8, 7.1, 15.5 mg/kg/day

Maternal NOAEL = 7.1 mg/kg/day

LOAEL = 15.5 mg/kg/day based on clinical signs anddecreased food consumption, body weight gains, and body

weight gains (adjusted for gravid uterine weight).

Developmental NOAEL = 15.5 mg/kg/day

LOAEL was not established.

870.3700b Prenatal

developmental in

rabbit (gavage)

00145997 (1984)


0, 2.36, 3.5, 7 mg/kg/day

Maternal NOAEL = 2.36 mg/kg/day, LOAEL = 3.5 mg/kg/day

based on treatment- related head and forelimb twitching.

Developmental NOAEL =7 mg/kg/day, LOAEL not established.


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Guideline/

Reference


870.3800 Reproduction and

fertility effects

(rat) 2-yr

00157225 (1986)


0, 1.5, 3.0, 5.0 mg/kg/day

Parental/Systemic NOAEL = M/F: 5.0/3.0 mg/kg/day,LOAEL

was not established in males. In females, LOAEL= 5.0

mg/kg/day based on tremors and decreased body weights.

Reproductive/ Offspring NOAEL = 5.0 mg/kg/day,

Reproductive/ Offspring LOAEL not established.

870.4100b Chronic toxicity

1-yr (dog)

00163065 (1985)


0, 0.66, 1.3, 2.7, 4.4 mg/kg/day

NOAEL = 1.3 mg/kg/day,

LOAEL= 2.7 mg/kg/day based on increased incidence of

tremors.

870.4300 Chronic/

Carcinogenicity 1-

yr (rat)

00157226 (1986)

Acceptable/guideline M: 0, 0.6, 2.3, 4.7, 9.7

mg/kg/day

F: 0, 0.7, 3.0, 6.1, 12.7 mg/kg/day

NOAEL = M/F: 4.7/3.0 mg/kg/day,

LOAEL =M/F: 9.7/6.1 mg/kg/day based on increased

incidence of tremors.

No conclusive evidence of carcinogenicity

870.4300 Chronic/

Carcinogenicity

(mouse)

00157227 (1986)


M: 0, 6.7, 25.6, 65.4, 81.3 mg/kg/day

F: 0, 8.8, 32.7, 82.2, 97.2 mg/kg/day

NOAEL =M/F: 6.7/8.8 mg/kg/day,

LOAEL = M/F: 25.6/32.7 mg/kg/day based on based on

increased incidence of tremors.

Carcinogenic potential was evidenced by a dose-related

increase in the incidence of leiomyosarcomas in the urinary

bladder, a significant dose-related trend for combined

hepatocellular adenomas and carcinomas in males, and a

significantly higher incidence of combined lung adenomas

and carcinomas in females.

870.6200a Acuteneurotoxicity-rat

(gavage)

44862102(1998)Acceptable/Guideline

0, 9.4, 32.8, 70.3 mg/kg/day

NOAEL = 32.8 mg/kg/day,LOAEL=70.3 mg/kg/day based on clinical signs of toxicity, FOB

findings, altered motor activity, and mortality (females only).

870.6200b Subchronic

neurotoxicity

screening battery

(rat)

44862103 (1998)

Acceptable/Guideline M: 0, 2.7, 5.6, 11.1

mg/kg/day

F: 0, 3.5, 6.7, 13.7 mg/kg/day

NOAEL= M/F: 2.7/3.5 mg/kg/day,

LOAEL= M/F: 5.6/6.7 mg/kg/day based on neuromuscular

findings (tremors, changes in grip strength and landing foot-

splay).


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Guideline/

Reference


870.6300 Developmental

Neurotoxicity

(rat)

46750501 (2006)

Acceptable/non-guideline

0, 3.6, 7.2 and 9.0 mg/kg/day (gestation)

0, 8.3, 16.2 and 20.7 mg/kg/day (lactation)

Maternal NOAEL = 3.6 mg/kg/day during gestation and 8.3

mg/kg/day during lactation, LOAEL = 7.2 mg/kg/day during

gestation and

16.2 mg/kg/day during lactation based on clinical signs of

neurotoxicity (tremors, clonic convulsions, and increased

grooming counts).

Developmental NOAEL =3.6 mg/kg/day during gestation and

8.3 mg/kg/day during lactation.

Developmental LOAEL = 7.2 mg/kg/day during gestation and

16.2 mg/kg/day during lactation based on clinical signs of

neurotoxicity (increased grooming counts).

Akhtar et al.

(1999)

5 Albino rats oral gavage 0.5 mg/d Talstar over 21 days Serum concentrations of T3 and T4 (P < 0.01) suppressed;

serum TSH concentrations increased (P < 0.01)

Holton et al.

(1997)

3 F344 rats 20 mg/kg at 6 h and 10 mg/kg at 24 h No histological changes in any part of the brain. Fine tremors

only (not enough to interfere with gross motor activities such

as eating etc.)

in vitro

Studies

JMPR 1992

citing:

Haworth

(1983);Kennelly et al.

(1988)

Mutagenicity;

Ames assay; S.

typhimurium

75 - 7500 g/plate; Negative with and without activation.

JMPR 1992

citing: Kirby

(1983)

Mouse lymphoma nonactivated 0.018 - 0.24 l/ml; activated

0.0075 - 0.1 l/ml

Positive at highest dose with activation; no dose-response.

JMPR 1992

citing:

Kennelly

(1986)

Mouse lymphoma 15.8 - 500 g/ml Negative with and without activation.


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Guideline/

Reference


JMPR 1992

citing:

Heidemann

(1989)

Chinese hamster

ovary cells

10 - 100 g/ml with and without activation Negative with and without activation.

JMPR 1992

citing:

Thilagar

(1984b)

Chinese hamster

ovary cells

chromosome

aberration

1000 - 10 000 g/ml with and without activation Negative with and without activation.

JMPR 1992

citing:

Thilagar

(1983a)

DNA repair (UDS)

rat primary

hepatocytes

0.01 - 2.0 l/ml Positive at highest dose; no dose-response.

JMPR 1992

citing:

Thilagar

(1983b)

DNA repair (UDS)

rat primary

hepatocytes

0.5 - 2.5 l/ml Negative

JMPR 1992

citing: Fautz

et al. (1989)

DNA repair (UDS)

rat primary

hepatocytes

1 - 100 g/ml Negative

JMPR 1992

citing:

Heidemann(1989)

Chinese hamster

ovary sister

chromatidexchange

1 - 60 g/ml with and without activation Negative

Goto et al.

(2004)

Bhas 42 cells

from BALB/c 353

mouse embryo

cells transfected

with v-Ha-ras

oncogene

0 - 5 ppm At least twice the foci of controls at approximately 2ppm;

zero foci at 5 ppm. Authors conclude evidence of a good

dose-response relationship; however, not clear on what basis

determination made.


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Guideline/

Reference


Goto et al.

(2004)

Modified Ames TA 100 and TA 98 with and without S9 activation Negative for mutagencity.

Liu et al.

(2008)

human amnion

epithelial (FL) cell

lines

7.5 - 60 mg/L 1S-cis-BF caused 3x higher cell apoptosis compared with 1R-

cis-BF; evidence for enantioselectivity.

Liu et al.

(2009)

cultured Hep G2

cells

5 - 40 mg/L Exposure to 1S-cis-BF resulted in increased levels of

phosphorylated JNK (Jun-N-terminal Kinases)/MAPKs, while

exposure to 1R-cis-BF did not affect phosphorylated JNK

levels.

Wang et al.

(2007)

E-SCREEN, ELISA 10-13

to 10-5

M; 10 ng/ml Increased proliferation of MCF-7 cells at 3.5 times control

peaked at 10-9

M for 1S-cis-BF, then decreased (but still

statistically significantly different from control); 1R-cis-BF was

1.5 times control across all concentrations. Response to 1S-

cis-BF was about 123 times greater for medaka vitellogenin

induction.

Hoffman et

al. (2006)

human CD4+ H9,

and Jurkat cell

lines and the

human

promonocyteU937 cell line

10-13

to 10-4

M Nontoxic at concentrations ranging from 104

to 1013

M. Did

not inhibit PHA induced cell aggregation in all cell lines

tested. At 104

M, stimulated homotypic aggregation in the

H9 and Jurkat T-cell lines. Aggregation blocked by treating

the cells with antibodies to either LFA-1 or ICAM.

Nandi et al.

(2006)

PC12 cells were

differentiated

with nerve

growth factor for

twenty-four

hours and then

treated for up to

an additional 48

hours

1010

M to 1104

M 105

M bifenthrin, approximately 80% of these neurites

retracted in within 12 additional hours and almost all

neurites had retracted within 48 hours but all cells were

viable.


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Guideline/

Reference


Tran et al.

(2006)

PC12 cells were

differentiated

with nerve

growth factor for

48 hours

10-13

to 10-4

M 107

M and 105

M bifenthrin, no reduction in cell viability but

neurite outgrowth reduced 30% and 55%.

Lu et al.

(2010)

PC12 cells 10-9

M to 10-5

M Significant reduction in cell survival and superoxide dimutase,

increased production of lactate dehydrogenase, intracellular

reactive oxygen species and malondialdehyde, was observed

in 1S-cis-BF; less so in 1R-cis-BF (only at 10-5

and no oxidative

damage)

ToxCast in vitroassays (see Table 3)


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nerve conduction, and electromyogram and no statistically significant differences were foundpre- and post-exposure. However, this study was strictly a short-term study, and did not addresspotential impacts of longer term, chronic exposures.

Carcinogenicity

As shown in Table 2, two unpublished rodent studies evaluated the potential carcinogenicity ofbifenthrin. Both studies were two-year chronic feeding studies, one in Swiss Webster mice andthe other in Sprague-Dawley rats. The mouse study found no significant differences in survivalbetween the groups of either sex. However, tumors were observed in the bladders of two andthree male mice at doses of 500 and 600 ppm respectively, and one female mouse at a dose of200 ppm. No dose-response relationship was observed in either case, although the male cancerswere marginally statistically significantly different from controls at the highest dose whenconsidering all doses (Butler et al. 1997). A reevaluation by Butler et al. (1997) found that thehistological features of the tumors based on smooth muscle and vascular differentiationsuggested a vascular origin. In addition, the authors observed a chronic inflammatory infiltrate

and hemosiderin associated with the tumors. There were no metastases observed across eithersex. The particular tumor type has since been identified as a submucosal mesenchymal lesion ofthe urinary bladder of the mouse (Butler et al. 1997; Halliwell 1998) with no relevance topotential human health risks. The other study in rats found no significant treatment-relatedeffects across all endpoints (Unpublished study, McCarty et al. 1986, as reported in JMPR 1992).

The US EPA conducted three separate peer review processes to determine the potentialcarcinogenicity of bifenthrin. All three peer reviews determined that bifenthrin was a CategoryC, possible human carcinogen, on the basis of two unpublished rodent studies. A jointinternational meeting of the Food and Agricultural Organization (FAO) Panel of Experts onPesticide Residues in Food and the Environment and the World Health Organization (WHO)

Expert Group on Pesticide Residues, with the cooperation of the International Programme onChemical Safety (IPCS) met in Rome in 1992 and concluded that although the tumor incidencein the mouse study was of marginal statistical significance, tumorigenic potential for bifenthrinin mice could not be excluded. However, they stopped short of considering bifenthrin acarcinogen in humans (JMPR 1992).

Chronic Toxicity

A number of unpublished studies have formed the basis for several different regulatory reviewswith respect to bifenthrin as shown in Table 2. DeProspo et al. (1986) as reported in JMPR(1992) administered bifenthrin in the diet at concentrations of 0, 30, 60 or 100 ppm (0, 1.5, 3 or 5

mg/kg/day) to groups of rats (25/sex/group) over two consecutive generations. No mortality wasobserved. At 100 ppm tremors were observed in first-generation lactating dams. First-generationfemales showed reduced body-weight gain on days 7 and 14 of the lactation period. Foodconsumption was depressed in the second generation group at 100 ppm in the males during asingle week of exposure. The treatment did not have any effects on the reproductive performanceor litter size, litter weight or survival of the progeny. Changes in organ weights at 100 ppmconsisted of an elevation of the brain weights of first-generation females. No histomorphologicalterations were observed in tissues from parental or weanling animals. Based on the incidence


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of tremors and marginally lower body weights resulted in a no observed effect level (NOEL) of 3mg/kg-day. A lowest observed effect level was not observed; therefore, the reproductive NOELwas determined to be 5 mg/kg-day (62 FR 62961).

Freeman et al. (1984b) as reported in JMPR (1991) and summarized in 62FR69261 orally

gavaged groups of rats (25 females/dose/group) on days 6 through 15 of gestation with doses of0, 0.5, 1 or 2 mg/kg bw/day. Estimation of dose levels were based on a previous pilotdevelopmental study in rats in which bifenthrin was administered in the diet at dose levels of 0,0.5, 1.0, 2.0, or 2.5 mg/kg-day during days 6 to 15 of gestation. Three of 10 rats at 2.5 mg/kg/daydied on days 14-15. Across both studies, tremors were noted at 2.0 mg/kg-day. There were nodifferences in mean body weight gains or food consumption with respect to the controls. Therewere no treatment-related differences from controls for reproductive parameters, includingpregnancy, number of corpora lutea, implantations, resorptions or litter size. Fetal malformationsoccurred only sporadically in all groups and without any observable dose-response relationship.The maternal NOEL in this study was 1.0 mg/kg-day, and the maternal LOEL is 2.0 mg/kg/daybased on sporadic tremors (gestation days 7 18). The fetal NOEL is >2 mg/kg-day for embryo

fetotoxicity.

A study by Freeman et al. (1984a) as reported in JMPR (1991) and summarized in 62FR62961gavaged groups of rabbits (20 females/dose/group) at 0, 2.7, 4 or 8 mg/kg-bw on days 7 through19 of gestation, based on an earlier dose range finding study. Tremors were observed for most ofthe animals receiving 8 mg/kg bw/day and head and fore limb twitching were observed duringthe second half of the dosing period among most of the animals receiving 4 or 8 mg/kg-bw. Thetest material did not affect the body-weight of the dams, the reproduction parameters, viability orbody-weight of the pups, nor the incidence of external and visceral anomalies. The maternalNOEL was estimated at 2.7 mg/kg-day, based on head and forelimb twitching at a LOEL of 4.0mg/kg/day. The developmental NOEL is 8.0 mg/kg/day, the highest dose tested.

JMPR 1992 reports on a study by Algate et al. (1985) in which groups of rats (COBS/Wistar; 3males/dose group) were orally treated with doses of 0, 1.0, 3.0, 10.0 or 30.0 mg/kg bw/day forconsecutive days. Parameters investigated included alertness, locomotor activity, apathy, tremorand abnormal gait. Rats at 30 mg/kg bw/day showed tremor, abnormal gait, respiratorydepression and signs of CNS depression (apathy, paralysis). Deaths occurred after developingconvulsions. No effects were recorded during the 7-day period after termination of dosing with 1,3 and 10 mg/kg-d.

The minimum effective dose of 30 mg/kg bw/day which caused neurological signs such asparalysis as determined in the Irwin dose-range test (Algate et al. 1985) was used in a tilting-plane test. The test compound was administered orally to groups of rats (5/sex) on twoconsecutive days. The tilting-plane test (parameter: angle of inclination at which the animalsbegan to slide down a tilted platform) was performed every second day from days 2-16 of thestudy. The results did not reveal impairment of performance by the treatment and this gave noindication of a delayed neurotoxic effect (Algate et al. 1985).

Aldridge (1990) provided an assessment of the toxicological properties of pyrethroids generallywith respect to their neurotoxicity and found that exposure of rats to pyrethroids at high doses


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(often doses that are also associated with death of the animal) led to minor lesions in nerve cellsthat were not observed at lower doses and were reversible given survival of the animal. Aldridge(1990) concluded that there were no observable neurotoxic actions of the pyrethroids other thanthose originating from their primary mechanism of action on the sodium channel, and thatpyrethroid exposure in working practice would not lead to chronic neurotoxicity.

Subclinical Effects

Akhtar et al. (1996) conducted a study to evaluate the effect of Talstar, (a commercialformulation of bifenthrin) and a number of other insecticides on the thyroid secretory function inrats. Five rats (ranging in weight from 240 320 g) were adminstered 0.5 mg Talstar via oralgavage for 21 days. Serum concentrations of triiodothyronine (T3), thyroxine (T4,) andthyrotrophin (TSH) were determined by using specific radioimmunoassays. Body weight wassignificantly reduced in Talstar-treated rats (P < 0.01) and serum T3 and T4 levels weresignificantly suppressed (P < 0.01), while TSH concentrations were stimulated (P < 0.01).

Hoffman et al. (2006) exposed human CD4+ H9, and Jurkat cell lines and the humanpromonocyte U937 cell line to bifenthrin and found that bifenthrin was nontoxic atconcentrations ranging from 104to 1013M. Bifenthrin did not inhibit PHA induced cellaggregation in all cell lines tested. However, at 104M, bifenthrin activated T-cell function bystimulating ICAM/LFA-1 mediated homotypic aggregation, suggesting that exposure tobifenthrin can increase the risk for and frequency of inflammatory responses. However, thatmolar concentration approximately corresponds to an in vivodose of 2.5 mg/kg-d, much higherthan predicted exposures (see below).

Given that bifenthrin is a known neurotoxicant, studies that have explored subclinicalneurotoxicological effects may be most relevant with respect to endpoints in humans. However,

the link between alterations in neuronal firing and downstream neurobehavioral syndromes iscorrelative and not causative (Wolansky et al. 2009). Van Tran et al. (2006) found thatbifenthrin inhibited neurite formation by 30% at concentrations of 10-7M (roughly equivalent to0.002 mg/kg-d). These authors argue that bifenthrin exposure in uterocould lead toneurodevelopmental defects and further argue the possibility that chronic exposure to bifenthrinmay lead to neurodegenerative disease (Tran et al. 2006; Nandi et al. 2006). However, boththese studies relied on the widely used PC12 cell line, which while exhibiting extensive neuriteoutgrowth upon differentiation, do not actually give rise to definitive axons or dendrites (Radioand Mundy 2008). The mechanistic basis of induction of differentiation in cell lines is not fullyunderstood, and neurite outgrowth may differ from that occurring in primary neurons. Forexample, neurites elaborated by the PC12 cell line do not exhibit the properties of either axons or

dendrites. Near-lethal doses of pyrethroids cause sparse axonal damage that is reversed insurviving animals. After prolonged exposure to lower doses of pyrethroids axonal damage hasnot been observed (Vijverberg et al. 1990) although this observation was not specific tobifenthrin.

The effects of pyrethroids on the CNS are complex and may also involve antagonism of -aminobutyric acid (GABA), modulation of nicotinic cholinergic transmission, enhancement ofnoradrenalin release, and direct actions on calcium or chloride ion channels. Still, because


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neurotransmitter-specific pharmacological agents do not protect very well against pyrethroidpoisoning, it is unlikely that any one of these effects represents a primary toxic mechanism ofaction of pyrethroids. More likely, they are secondary to the effects on sodium channels sincemost neurotransmitters are released secondary to increased sodium entry (Bjorling et al. 2008).

There is some concern that some synthetic pyrethroids may possess estrogenic properties (Go etal. 1999). However, with respect to potential effects on thyroid function, the effects are notconsistent. In an oral gavage study with Talstar (a commercial bifenthrin formulation), Akhtaret al. (1999) found reduced serum concentrations of thyroid hormones after one week ofcontinuous exposure, while Kaul et al. (1996) found exactly the opposite effect . A key concernwith thyroid inhibitors is that impaired thyroid function may alter hormone-mediated eventsduring development, leading to permanent alterations in brain morphology and function. Theimplication for human effects may be revealed through studies such as Hauser et al. (1993), whodemonstrated a possible relationship between thyroid hormone dysfunctions and ADHD byshowing that a majority of children with resistance to thyroid hormone (RTh) exhibited ADHD-like symptoms (note: unrelated to bifenthrin in any way). Stein and Weiss (2003) have shown

that thyroid hormone concentrations, in children referred to a clinic specializing in learning andbehavioral problems, were associated with attentional deficits and hyperactivity and that theADHD subtype, primarily inattentive, was associated with reductions in free thyroid hormoneconcentrations. However, there is only one positive study (Akhtar et al. 1999), and that study hadvery little power (five rats total), and the dose mechanism was oral gavage (as opposed to in thediet, which would represent a more relevant exposure route for humans), the effect was notconsistent across studies involving individual pyrethroids, and the statistical significance wasborderline (P < 0.01). Finally, as pointed out by McClain (1992), species-specific differences inthyroid gland biochemistry and physiology, notably the lack of thyroid binding globulin in therodent, urges caution in evaluating hormonally-mediated responses involving thyroid function.

US EPA ToxCast Assay Results

Table 3 shows the ToxCast assays conducted by the US EPA (Wetmore et al. 2012; Judson et al.2010; Rotroff et al. 2010). Approximately 400 chemicals, including bifenthrin, were subjectedto nearly 500 high-throughput in vitrohuman cell culture screens for assessing potential effectsacross multiple cellular pathways. The authors experimentally measured metabolic clearanceand plasma protein binding to parameterize a population-based in vitro-to-in vivoextrapolationmodel for estimating the human oral equivalent dose necessary to produce a steady-state in vivoconcentration equivalent to in vitroAC50 (concentration at 50% of maximum activity) and LEC(lowest effective concentration) values from the ToxCast data. The assays range from enzymeinduction in specific kinds of cells to up- and down-regulation of different genes.

The assay at which effects were noted at the lowest equivalent in vivodose was for observablechanges in cell growth kinetics, followed by unspecified protein binding. It is not clear whatrelevance these subclinical effects have with respect to in vivoeffects, but a number of the assayresults at higher concentrations would seem to support some of the immunotoxic effects noted inTran et al. (2006) and elsewhere. However, these effects may be occurring at doses greater thanwould typically be experienced by the general population (see next section).


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Table 3: ToxCast Assay Results

ToxCast Assay (Judson et al.

2011)

Lowest Oral

Equivalent

Dose (mg/kg-d)

Median Oral

Equivalent

Dose (mg/kg-d)

Upper Oral

Equivalent

Dose (mg/kg-d)

Assay Description

ACEA_LOCinc 0.01 0.02 0.04 Change in cell growth kinetics

NVS_TR_hNET 0.01 0.03 0.06 Protein binding; biochemical

BSK_3C_Vis_down 0.04 0.09 0.16 Unknown

BSK_BE3C_uPA_down 0.04 0.09 0.16 This gene encodes a serine protease involved in

degradation of the extracellular matrix; possibly tumorcell migration and proliferation. Polymorphism

associated with late-onset Alzheimer's; decreased

affinity for fibrin-binding.

BSK_hDFCGF_MMP1_up 0.04 0.09 0.16 Upregulation of protein involved in the breakdown of

extracellular matrix in normal physiological processes.

BSK_KF3CT_MMP9_down 0.04 0.09 0.16 Downregulation of protein involved in the breakdown of

extracellular matrix in normal physiological processes.

BSK_SAg_CD38_up 0.04 0.09 0.16 Upregulation of CD38; novel multifunctional ectoenzyme

widely expressed in cells and tissues especially in

leukocytes. Cell adhesion, signal transduction and

calcium signaling.

ATG_PXR_TRANS 0.11 0.24 0.44 This gene product belongs to the nuclear receptor

superfamily, members of which are transcription factors

characterized by a ligand-binding domain and a DNA-

binding domain. The encoded protein is a transcriptionalregulator of the cytochrome P450 gene CYP3A4, binding

to the response element of the CYP3A4 promoter as a

heterodimer with the 9-cis retinoic acid receptor RXR. It

is activated by a range of compounds that induce

CYP3A4.

CLZD_CYP1A1_48 0.12 0.25 0.44 Encodes a member of the cytochrome P450 superfamily

of enzymes.

BSK_hDFCGF_MCSF_down 0.12 0.26 0.47 Downregulation of a gene encoding a cytokine protein

that controls the production, differentiation, and

function of macrophages.


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2011)

Lowest Oral

Equivalent

Dose (mg/kg-d)

Median Oral

Equivalent

Dose (mg/kg-d)

Upper Oral

Equivalent

Dose (mg/kg-d)

Assay Description

BSK_hDFCGF_Proliferation_dow

n

0.12 0.26 0.47 Downregulation; dermal fibroblast.

BSK_hDFCGF_VCAM1_up 0.12 0.26 0.47 Upregulation of a member of the Ig superfamily that

encodes a cell surface sialoglycoprotein expressed by

cytokine-activated endothelium. This type I membrane

protein mediates leukocyte-endothelial cell adhesion

and signal transduction, and may play a role in the

development of artherosclerosis and rheumatoid

arthritis.

BSK_SAg_CD69_down 0.12 0.26 0.47 Downregulation of calcium dependent lectin superfamily

of type II transmembrane receptors. Expression of the

encoded protein is induced upon activation of T

lymphocytes, and may play a role in proliferation.

CLZD_CYP2B6_48 0.12 0.26 0.48 Encodes a member of the cytochrome P450 superfamily

of enzymes.

CLZD_CYP3A4_48 0.13 0.27 0.49 Encodes a member of the cytochrome P450 superfamily

of enzymes.

CLZD_GSTA2_48 0.14 0.30 0.55 Enzymes that function in the detoxification of

electrophilic compounds.

CLZD_CYP2B6_24 0.19 0.39 0.70 Encodes a member of the cytochrome P450 superfamily

of enzymes.CLZD_CYP3A4_24 0.25 0.52 0.92 Encodes a member of the cytochrome P450 superfamily

of enzymes.

BSK_3C_hLADR_down 0.28 0.58 1.03 Downregulation of a gene in the immune system by

presenting peptides derived from extracellular proteins.

BSK_3C_Proliferation_down 0.28 0.58 1.03 Downregulation.

BSK_3C_Thrombomodulin_up 0.28 0.58 1.03 Upregulation of endothelial-specific type I membrane

receptor that binds thrombin. This binding results in the

activation of protein C, which degrades clotting factors

Va and VIIIa and reduces the amount of thrombin

generated.


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2011)

Lowest Oral

Equivalent

Dose (mg/kg-d)

Median Oral

Equivalent

Dose (mg/kg-d)

Upper Oral

Equivalent

Dose (mg/kg-d)

Assay Description

BSK_4H_Pselectin_down 0.28 0.58 1.03 Downregulation of selectin P (granule membrane protein

140kDa, antigen CD62).

BSK_4H_VCAM1_down 0.28 0.58 1.03 Downregulation of a member of the IG superfamily.

BSK_hDFCGF_CollagenIII_up 0.28 0.58 1.03 Upregulation of pro-alpha1 chains of type III collagen, a

fibrillar collagen that is found in extensible connective

tissues such as skin, lung, uterus, intestine and the

vascular system, frequently in association with type I

collagen.

BSK_LPS_IL8_down 0.28 0.58 1.03 Downregulation of a member of the CXC chemokine

family. This chemokine is one of the major mediators of

the inflammatory response.

BSK_LPS_MCSF_down 0.28 0.58 1.03 Downregulation of a cytokine that controls the

production, differentiation, and function of

macrophages.

BSK_LPS_PGE2_down 0.28 0.58 1.03 Downregulation of prostaglandin E receptor 2 (subtype

EP2).

BSK_LPS_VCAM1_down 0.28 0.58 1.03 Downregulation of a member of the IG superfamily.

BSK_SAg_Eselectin_down 0.28 0.58 1.03 Downregulation of cytokine-stimulated endothelial cells;

thought to be responsible for the accumulation of blood

leukocytes at sites of inflammation by mediating the

adhesion of cells to the vascular lining.BSK_SAg_IL8_down 0.28 0.58 1.03 Downregulation of CXC chemokine family; major

mediators of the inflammatory response.

BSK_SAg_PBMCCytotoxicity_up 0.28 0.58 1.03 Increased cytotoxicity.

BSK_SAg_Proliferation_down 0.28 0.58 1.03 Decreased proliferation.

ATG_PXRE_CIS 0.29 0.60 1.08 Transcriptional regulator of cytochrome P450 gene.

CLZD_ABCB1_24 0.31 0.64 1.15 ABC proteins transport various molecules across extra-

and intra-cellular membranes.

ATG_VDRE_CIS 0.43 0.91 1.62 Cytochrome P450.

CLZD_CYP1A1_24 0.57 1.19 2.13 Cytochrome P450.


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2011)

Lowest Oral

Equivalent

Dose (mg/kg-d)

Median Oral

Equivalent

Dose (mg/kg-d)

Upper Oral

Equivalent

Dose (mg/kg-d)

Assay Description

NCGC_PXR_Agonist_human 0.59 1.23 2.20 Transcriptional regulator of the cytochrome P450 gene

CYP3A4.

ACEA_LOC2 0.68 1.43 2.56 Change in cell growth kinetics

ACEA_LOCdec 0.68 1.43 2.56 Change in cell growth kinetics

ACEA_IC50 0.71 1.48 2.65 Change in cell growth kinetics

ATG_ERa_TRANS 0.76 1.60 2.86 Estrogen receptor, a ligand-activated transcription factor

composed of several domains important for hormone

binding, DNA binding, and activation of transcription.

BSK_3C_MCP1_down 0.83 1.73 3.09 Family of secreted proteins involved in

immunoregulatory and inflammatory processes.

BSK_4H_Eotaxin3_down 0.83 1.73 3.09 Downregulation of gene coding proteins involved in


BSK_4H_MCP1_down 0.83 1.73 3.09 Downregulation of gene coding proteins involved in


BSK_hDFCGF_PAI1_down 0.83 1.73 3.09 Unknown

BSK_SAg_CD40_down 0.83 1.73 3.09 Downregulation of a gene mediating a broad variety of

immune and inflammatory responses including T cell-

dependent immunoglobulin class switching.

BSK_SM3C_Proliferation_down 0.83 1.73 3.09 Human vascular cells downregulation of proliferation.

CLM_Hepat_DNADamage_48hr 1.24 2.60 4.65 DNA damage in rat hepatocytes.

CLM_CellLoss_72hr 2.67 5.58 10.00 Cell loss in rat hepatocytes.

CLM_MicrotubuleCSK_72hr 3.02 6.31 11.31 Microtubule damage in rat hepatocytes.

CLM_Hepat_Steatosis_48hr 3.86 8.06 14.44 Steatosis in rat hepatocytes.

CLM_MitoMembPot_1hr 4.08 8.51 15.26 Mitochondrial function in HepG2 rat hepatocytes.


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Regulatory Toxicity Values and Equivalent in vivoDoses Associated with in vitroEffects

Table 4 presents the range of regulatory values used to develop risk assessments in the UnitedStates and Europe as part of pesticide registration activities. In general, these values are all

based on a NOAEL, e.g., a dose at which no effects were observed in the original study, of 1.5mg/kg-d from the one-year feeding study in dogs (EPA 1988; Serota et al. 1985 as cited in JMPR1992) but incorporating different safety factors (typically 100 - 300). These doses, designed tobe protective of any potential health effects of exposure to bifenthrin given that they are based ona no effect level, are in the 0.004 to 0.03 mg/kg-d range. The duration column shows over whattime period these exposures can occur -- long-term (e.g., lifetime), medium-term (e.g., a year ortwo), or short-term (e.g., days).

We estimated equivalentin vivodoses fromtoxicological studies toexplore whethersubclinical effects notedthrough in vivoand invitrotoxicologicalstudies might occur atrelevant exposure

concentrations. The methodology is based on the extensive physiological basedpharmacokinetic (PBPK) modeling performed as part of the US EPA ToxCast program(Wetmore et al. 2012; Rotroff et al. 2010; Judson et al. 2010). These authors conductedmodeling to be able to convert in vitroToxCast assay results to equivalent in vivoexposureconcentrations. Table 3 presents those values for bifenthrin and the various ToxCast assays.The lowest concentration associated with any assay is 0.01 mg/kg-d for potential effects on cellgrowth. This value is at the high end of the regulatory range shown in Table 4.

Going back to Table 2, there are a number of in vitrostudies, particularly for neurotoxicendpoints, that noted effects, but typically at concentrations in the 10-4to 10-5M range, whichtranslate to equivalent in vivo concentrations of 1-10 mg/kg-d, significantly higher than theregulatory values. However, Tran et al. (2006) in their study involving the PC12 neuronal cellline found bifenthrin inhibited nerve growth factor-mediated neurite outgrowth by 30% and 55%at concentrations of 10-7and 10-6, respectively, and that concentrations of technical gradebifenthrin of 106M and 103M inhibited neurite outgrowth by approximately 35% and 75%respectively. Following the approach of Wetmore et al. (2012), the equivalent in vivodose at thelowest 10-7M concentration would be 0.002 mg/kg-d, lower than the lowest regulatory value.

Source Value (mg/kg-d) Duration

US EPA IRIS 0.015 long-term, lifetime exposures

US EPA 2003 0.004 long-term, lifetime exposuresUS EPA 2003 0.033 short-term exposures

EC 2010 0.015 short-term exposures

EC 2010 0.0075 medium-term exposures

EC 2010 0.0075 long-term, lifetime exposures

Table 4: Regulatory Values Used in Risk Assessments


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Comparison of Toxicity Values to Predicted Exposures

This section compiles predicted exposure estimates from risk assessment models developed bythe US EPA (US EPA 2011) and the European Commission (EC 2010). Specific details of thatmodeling is presented in those documents and not repeated here, but these are regulatory

evaluations designed to predict exposures protective of both applicators and the general publicacross a wide variety of uses of bifenthrin. The EC estimates are based on a biocidal use ofbifenthrin in which applicators are exposed via the inhalation and dermal pathways throughprofessional use of a water-based formulation containing 0.03% bifenthrin. The analysisassumes 11.4% absorption via the dermal pathway (by far the majority of the exposure) and100% absorption via the inhalation pathway. Oral exposure is assumed to be negligible in thiscase. For the general public using bifenthrin as a wood preservative, the EC analysis assumessome oral exposure following application of the bifenthrin, in addition to dermal and inhalationexposures. Oral absorption is assumed at 50%.

For the US EPA exposure estimates, dermal, oral, and inhalation are included, where oral also

includes potential residues on agricultural products (agricultural use is not authorized in Europe).

Figure 2 presents the compiled exposure estimates with the regulatory toxicity values in differentcolors (violet = 0.002 mg/kg-d from Tran et al. 2006; red = 0.004 mg/kg-d from US EPA 2003;blue = 0.0075 mg/kg-d from EC 2010, and green = 0.015 from EC 2010). The short-term valueof 0.03 from US EPA 2003 is not shown as it is much higher than any other value on the graph.

The top half of the graph shows predicted exposure estimates for "direct" exposures -- includingprofessional applicators (top four scenarios) or home residential use. The bottom part of thegraph below the gray line shows predicted exposures for "indirect" uses -- home residential andgarden use involving professional applications and residual exposures to individuals in the home.

The range of values presented for the EC study in the top half of the graph are based professionalapplicators using bifenthrin with protective gear (lowest values) to no protective gear (highestvalues).

In general, predicted exposures for the general population fall below any regulatory levels ofconcern. The violet line is a subclinical effect and is only included because it is the onlyevidence of any effects occurring at concentrations that might relevant to potential exposures.The red and blue lines are based on a no observed adverse effect level, and the green line,protective of short term exposures, is based on an observation of tremors in rats. Applicatorswho fail to use protective gear do exceed the regulatory NOAEL, but fall short of actual effectlevels. In addition, the use of bifenthrin as a biocide on wood involves an application method

likely to be very different from what is experienced in the United States, where the primary useof bifenthrin is as a direct-acting insecticide (e.g., sprayed into crevices, etc.) or on agriculturalcrops to which the general public would only be exposed through residues.


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Conclusions

The available studies for bifenthrin suggest a low probability of adverse health effects associated

with exposure at environmentally-relevant concentrations. For cancer, specifically bladdercancer, as an endpoint, of the two chronic two-year rodent studies, the one in mice showed amarginally statistically significant increase in a type of vascular bladder cancer. Three separateand independent peer reviews convened by EPA concluded that bifenthrin was a class C,possible human carcinogen, on the basis that the particular observed tumor was rare, butconsidering the ameliorating factors that no dose response relationship was observed, the onlyincidence of the tumor that was statistically significant (marginally so) was at the highest dose,and that the tumors were only observed in males, the panel could not conclude that bifenthrinwas carcinogenic although did not rule it out, either. The rat study showed no increases intumors of any kind. A joint international meeting of the Food and Agricultural Organization(FAO) Panel of Experts on Pesticide Residues in Food and the Environment and the World

Health Organization (WHO) Expert Group on Pesticide Residues, with the cooperation of theInternational Programme on Chemical Safety (IPCS) which met in Rome in 1992 concluded thatbifenthrin is not carcinogenic and shows no evidence of mutagenicity. The results of in vitroandin vivotest results that predict human carcinogenicity support a determination that the evidencefor bifenthrin exposure leading to carcinogenic outcomes in humans is marginal to non-existent.

A series of studies using the rat PC12 cell line found statistically significant decreases in neuriteoutgrowth at the highest concentration tested, but with concomitant cell viability, indicating no

Figure 2: Estimated Exposure Levels (mg/kg-d) from US EPA (2003) and EC (2010) Under Regulatory Evaluations of

Bifenthrin. Reference Lines are Violet (Tran et al. 2006 Subclinical Effects); Red (US EPA 2003 for Chronic Exposures);

Blue (EC 2010 and US EPA IRIS); Green (EC 2010 Short Term Exposures)


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neuronal cell death, a prerequisite for neurodegenerative effects in humans. Consequently, theevidence for chronic neurotoxicological effects in humans is marginal to non-existent. The USEPA recently published a cumulative risk assessment for the synthetic pyrethroids generally andfocused on short-term neurotoxicological impacts related solely to disruption of sodium-gatedchannels and found that the cumulative impact of synthetic pyrethroids allowed for additional

risk in the "risk cup" (US EPA 2011).

A number of studies have demonstrated enantiospecific toxicity (attributable to 1R-cis-bifenthrin); however, given that most commercial mixtures will likely contain some proportionof both enantiomers and so the contribution of any one is difficult to predict. Similarly, theToxCast assay results did not specify which enantiomer was used, and different results couldhave been observed across one or the other.

Both the US EPA (2011) and the European Commission (2010) have estimated potentialexposures to bifenthrin as part of regulatory evaluations. Comparing these predicted exposuresto regulatory toxicological levels shows that only exposures to applicators who directly handle

bifenthrin, and typically assuming no protective gear, are likely to exceed regulatory values.These regulatory values are derived from a study in dogs and are based on a NOAEL withuncertainty and safety factors. The regulatory values are an order of magnitude lower than thelowest value from a series of 500 human cell culture assays (ToxCast). The ToxCast results alsoshowed that bifenthrin induces P450 metabolism, typically a detoxifying mechanism, although atconcentrations higher than predicted by regulatory exposure models. However, were exposuresto be underestimated or were to increase, these metabolic pathways would serve to detoxify theparent compound as has also been observed in the in vivopharmacokinetic studies summarizedin Table 1.

Bifenthrin is a synthetic derivative of a pyrethroid found in crysanthemums. The syntheticderivative is specifically designed such that the mechanism for acute toxicity preferentiallyselects the target organism, thereby reducing potential toxicity to mammals, and toxicity tomammals is an order of magnitude less than to target organisms (US EPA 2011). The risk ofadverse health effects resulting from chronic exposures is judged to be low based on themarginal to non-existent evidence for health effects; nonetheless this low risk must be consideredin the larger context of the benefits received from use of the constituent in products toexterminate pests, primarily termites. Given the utility and efficacy of bifenthrin with respect toits termiticidal properties, the analysis qualitatively suggests a net positive risk-benefit tradeoff.

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