Research | Articles

Fenitrothion: Toxicokinetics and Toxicologic Evaluation in Human Volunteers

Jean Meaklim,1 Jinming Yang,1 Olaf H. Drummer,2 Sheila Killalea,1 Voula Staikos,2 Soumela Horomidis,2
David Rutherford,3 Lisa L. Ioannides-Demos,1 Stephen Lim,1 Allan J. McLean,4 and John J. McNeil1
1Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia; 2Victorian Institute of Forensic
Medicine and the Department of Forensic Medicine, Monash University, Melbourne, Australia; 3Pathology Department, Alfred Hospital,
Melbourne, Australia; 4Clinical Pharmacology Department, Alfred Hospital, Melbourne, Australia

evening). Dose level 2 was 0.36 mg/kg/day

An unblinded crossover study of fenitrothion 0.18 mg/kg/day [36 times the acceptable daily (72 × ADI). The two dosing periods were
intake (ADI)] and 0.36 mg/kg/day (72 × ADI) administered as two daily divided doses for 4 days separated by at least 2 weeks, and up to 5
in 12 human volunteers was designed and undertaken after results from a pilot study. On days 1 months with some participants. The study
and 4, blood and urine samples were collected for analysis of fenitrothion and its major metabo- commenced in November 1994 and was
lites, as well as plasma and red blood cell cholinesterase activities, and biochemistry and hematol- completed by May 1995.
ogy examination. Pharmacokinetic parameters could only be determined at the higher dosage, as Participants. Twelve healthy adult volun-
there were insufficient measurable fenitrothion blood levels at the lower dosage and the fenitro- teers were recruited from among the scientific
oxone metabolite could not be measured. There was a wide range of interindividual variability in and medical communities in Melbourne,
blood levels, with peak levels achieved between 1 and 4 hr and a half-life for fenitrothion of Australia. Eight were male and four were
0.8–4.5 hr. Although based on the half-life, steady-state levels should have been achieved; the area female, with ages ranging from 23 to 50 years
under the curve (AUC)0–12 hr to AUC0–∞ ratio of 1:3 suggested accumulation of fenitrothion. (mean 33 years). Before commencing the
There was no significant change in plasma or red blood cell cholinesterase activity with repeated study, participants underwent a medical
dosing at either dosage level of fenitrothion, and there were no significant abnormalities detected examination and biochemical screens (includ-
on biochemical or hematologic monitoring. Key words: fenitrothion, pesticides, pharmacokinetics, ing plasma cholinesterase levels) to confirm
toxicity. Environ Health Perspect 111:305–308 (2003). doi:10.1289/ehp.5726 available via suitability for inclusion. Volunteers were
http://dx.doi.org/ [Online 30 October 2002] required to be otherwise healthy and have
normal baseline blood tests for hematology,
organ function, biochemistry profile, and
Fenitrothion is a broad spectrum organic in toxicity between humans and animals. cholinesterase activity.
phosphorothiate (organophosphate) insecti- Because of the widespread human exposure to Protocol. All clinical procedures were con-
cide used to protect fruit, vegetables, and fenitrothion, it is important to have more direct ducted in The Alfred Hospital, Department
grain crops. In Australia it has been widely evidence of the agent’s kinetic behavior and the of Clinical Pharmacology in Melbourne. After
used to protect stored grain, whereas in many relationship between plasma level and toxicity. an overnight fast, individuals received a single
tropical countries it has found extensive use This study was established to examine the dose of fenitrothion (formulated as a capsule
as a residual spray in homes for malaria con- kinetics of fenitrothion in humans after single and given with food) equivalent to one-half
trol. Its popularity stems from the high and repeated dosing and to relate the observed the daily dose. Blood samples were drawn pre-
potency and broad spectrum of its insecticide plasma levels to suppression of plasma and red dose for measurement of fenitrothion and its
action, its chemical stability, and its low blood cell cholinesterase levels. The subjects metabolites and at 1, 2, 3, 4, 6, 8, 10, and 12
acute mammalian toxicity. were selected from volunteers chosen hr after the first dose on day 1 and at similar
Because of its widespread use on stored because of their high level understanding of times after the morning dose on day 4. Blood
grain, fenitrothion is the most common toxicology and selection was approved by was also drawn predose and at 4 and 8 hr after
insecticide residue in Australian food. Surveys the Ethics Committee at Monash University dosing for measurement of whole blood and
undertaken during the 1980s showed the in Australia. All subjects underwent careful plasma cholinesterase levels. Urine was col-
daily intake of fenitrothion among individu- hematologic and biochemical monitoring. lected over a 24-hr period on days 1 and 4.
als consuming reasonable quantities of cere- Subjects were observed in the department
als, bread, and other grain-based foods could Materials and Methods for 12 hr on days 1 and 4, with regular blood
come close to the upper end of the Food and Pilot study. In an initial pilot study, three pressure measurement and regular question-
Agriculture Organization of the United adult males (mean age 45 years) ingested sin- ing about the presence of adverse effects.
Nations (FAO)/World Health Organization gle doses of fenitrothion at dose levels of Biochemical and hematologic parameters
(WHO) acceptable daily intake (ADI) of 0.06, 0.18, and 0.36 mg/kg (12, 36, and 72 ×
0.0–0.005 mg/kg body weight/day (1). ADI, respectively). Doses were separated by Address correspondence to J.J. McNeil, Department
During the 1990s, however, residue levels at least 2 weeks. Blood samples were collected of Epidemiology and Preventive Medicine, Monash
have declined, and the 1996 Australian at intervals over the subsequent 4 days for the University, Level 3, 553 St. Kilda Road, Melbourne
Market Basket survey suggested the average analysis of fenitrothion, fenitrooxon, and 3004, Australia. Telephone: 03 9903 0555. Fax: 03
9903 0556. E-mail: [email protected]
intake among young children was approxi- plasma cholinesterase levels. Urine was col- We acknowledge the nursing assistance of C.
mately 12% of the ADI, whereas that in lected for 2 days, and biochemical and hema- Woodburn, S. Gardiner, F. Williams, B. Clifford,
adults was approximately 4% of the ADI (2). tologic monitoring was also performed during and T. Mariner, and the medical assistance of J.
The ADI for a chemical is the highest level the course of the study. Beach, as well as AMCOSH (Advice Measurement
of consumption believed to cause no adverse Main study design. Twelve adult volunteers & Control in Occupational Safety & Health), for
health effects over a lifetime of exposure. For received each of two dose levels of fenitrothion, cholinesterase estimations and Melbourne Pathology
for full blood examinations.
fenitrothion, it is based on studies in rodents formulated as capsules and taken with food This study was partially funded by a grant from
that have established a no-observed adverse over 4 days. Dose level 1 was 0.18 mg/kg/day Sumitomo Chemical Co, Ltd., Japan. J. M. was a
effect level to which a safety margin is applied (36 × ADI) administered as two divided Victorian Health Promotion Foundation Scholar.
to account for possible interspecies differences doses given at 12-hr intervals (morning and Received 17 April 2002; accepted 9 August 2002.

Environmental Health Perspectives • VOLUME 111 | NUMBER 3 | March 2003 305

Articles | Meaklim et al.

were measured predose on day 1 and 3 days M HCl to convert conjugated MNP to free maximum concentration (Tmax), the maxi-
after the completion of each dosing period. MNP. MNP was then extracted with butyl mum fenitrothion concentration (Cmax), the
On days 2 and 3 of each dosing period, the chloride and acetylated with acetic anhy- half-life (t1/2), and the area under the curve
study coordinator or study nurse contacted dride, and the derivative was extracted with (AUC). To calculate AUC0–∞ when results
participants daily to deliver capsules and to butyl chloride. The reconstituted solvent was for plasma samples were not detectable, half
ensure compliance with the study protocol. chromatographed on a 15-m BP-5 capillary the not-detectable value was entered for the
Formulation of fenitrothion capsules. column using splitless injection and a nitro- first value and zero for subsequent values.
Fenitrothion capsules were manufactured in gen-phosphorus detector. Pentobarbitone
Melbourne by The Institute of Drug was used as an internal standard. Results
Technology from technical-grade fenitrothion The detection limit of this method from 1 Pilot study. No significant symptoms or
supplied by Sumitomo Chemical Company mL urine was 0.25 mg/L, although some adverse effects were observed among the vol-
Ltd. (Osaka, Japan). Capsules were formu- specimens had a slightly higher limit because unteer participants, and cholinesterase levels
lated in accordance with the Code of Good of sample volume and small background were not suppressed below 70% of predose
Manufacturing Practice (3) and kept refriger- interferences. Intraassay precision and interas- levels in any subject. Only limited informa-
ated prior to dispensing. say reproducibility were 6% at a concentration tion was available on plasma fenitrothion or
Analysis. Fenitrothion was extracted from of 8.0 mg/L. its oxon metabolite because of difficulties
acidified whole blood with butyl chloride. Plasma and red blood cell cholinesterase experienced with the assay development. The
After evaporation of the solvent, the reconsti- levels were determined by the Michel method available data indicated the half-life of feni-
tuted extract was chromatographed on a BP-5 (4), which measures the change in pH of a trothion and its oxon metabolite were of the
capillary column (J&W Scientific, Melbourne, blood mixture over time (units in ∆pH/hr). order of 3–6 hr, and the high urinary recov-
Australia) and the response measured with Ethics. The research protocol was approved ery of MNP suggested there were unlikely to
a nitrogenphosphorus detector (Agilent by the Monash University Ethics Committee. be substantial levels of other metabolites pre-
Technologies, Melbourne, Australia). Diazinon Participants were provided with a Plain sent in humans. It was expected that steady-
was used as an internal standard to correct for Language Statement plus a complete study pro- state levels of fenitrothion and its metabolites
variation in recovery. Detection limits were tocol. They were recruited from a group with would be achieved after relatively brief expo-
0.1–0.4 ng/mL, and assay precision was 17% at sufficient scientific knowledge to evaluate the sure to these compounds.
0.3 ng/mL, 13% at 0.6 ng/mL, and 5.8% at toxicologic issues and risks of the study and Main study. Fenitrothion levels. Whole-
1.0 ng/mL. Accuracy at all concentrations was were provided with the option of discussing blood concentrations of fenitrothion on days 1
± 20%, and reproducibility of fenitrothion at these with an independent physician. All and 4 after each of the two dosing schedules
these concentrations (n = 17–20) was 16, 7.5, participants gave written informed consent. are shown in Tables 1 and 2. As there were
and 8.6%, respectively. Fenitrothion was stable Pharmacokinetic analysis. The plasma insufficient measurable fenitrothion blood lev-
when stored at –20°C over a 6-month period. concentration time data were entered into els at the lower dose, the mean blood concen-
The levels of the metabolite 3-methyl-4- WinNonlin (Version 3.0; Pharsight tration–time data are presented only for the
nitrophenol (MNP) in urine were measured Corporation, Mountain View, California, higher dose (Figure 1). Principal toxicokinetic
after hydrolysis of the urine samples with 8 USA) to calculate the time to achieve parameters are summarized in Table 3.

Table 1. Fenitrothion plasma concentrations (ng/mL): dose 1 (0.18 mg/kg/day fenitrothion).

Time (hours postdose)
Subject 0 0.5 1 2 3 4 6 8 10 12 D/L
Day 1
001 a b a a a a a a a a 0.10
002 a 0.59 1.08 0.55 0.44 a a a a a 0.10
003 a b a a a a a a a a 0.20
004 a b 0.12 1.12 0.88 0.78 b 0.31 a a 0.10
005 a b 0.54 a a a a a a a 0.20
006 a 0.57 0.74 0.42 a a a a a a 0.20
007 a b a 0.42 a 0.87 0.33 a a a 0.40
008 a b a a a a a a a a 0.10
009 a b a a a a a a a a 0.20
010 a b 0.88 0.24 a a a a a a 0.10
011 a b 1.30 a a a a a a a 0.20
012 a b 0.77 a 0.52 a a a a a 0.20
Day 4
001 1.42 b 2.10 0.66 0.54 0.40 0.39 0.31 a a 0.10
002 a b a 0.32 a a a a a a 0.10
003 a b 0.20 a a a a a a a 0.20
004 1.48 b 2.97 2.89 2.20 2.90 1.00 0.71 0.48 0.36 0.10
005 a b 0.86 0.32 0.78 0.50 a a a a 0.20
006 a b 0.35 0.48 0.43 a a a a a 0.20
007 0.42 b 1.02 1.30 0.57 0.51 0.55 a a a 0.40
008 0.14 b 0.58 0.24 0.11 0.12 a a a a 0.10
009 a b a a a a a a a a 0.20
010 a b 0.48 1.16 0.33 0.24 a a a a 0.10
011 a b a a a a a a a a 0.20
012 a b 1.04 0.43 0.54 0.62 0.38 0.25 a a 0.20
D/L, detection limit of assay.
aNot detected. bNo sample was obtained.

306 VOLUME 111 | NUMBER 3 | March 2003 • Environmental Health Perspectives

 Articles | Fenitrothion toxicity in humans

Fenitrothion concentrations showed high Urine 3-methyl-4-nitrophenol. MNP was Cholinesterase level. Plasma and red cell
interindividual variation, with four subjects detected in all but one of the 24-hr urine cholinesterase activity recorded during the
having all levels below the limit of detection specimens analyzed (Table 4). After adjusting study were all within the normal range quoted
after the first day of the lower doses, and two for the molar equivalent of MNP to feni- for the healthy adult exposed population (i.e.,
others having no identifiable levels with the trothion, the MNP excretion corresponded to 0.60–1.10 ∆pH/hr in red cells, 0.62–2.0
lower dose on day 4. All subjects had 83 and 67% of the total fenitrothion dose ∆pH/hr in plasma). No statistically significant
detectable levels with the higher dose on day consumed on days 1 and 4 of the lower dose, trends were observed in mean plasma or red
1 and day 4, though five subjects had only and 97 and 76% of that consumed on days 1 blood cholinesterase levels. There were no
one to two detectable levels after the first and 4 of the higher dose, respectively. individual cases where cholinesterase activity
dose. Fenitrothion was cleared and metabo-
lized from the blood too fast to obtain valid 12
concentrations in a sufficient number of vol- Dose 2 day 1
Dose 2 day 4
unteers at the lower dose; therefore, valid cal-
culation of kinetic parameters was possible 10

Fenitrothion plasma concentrations (ng/mL)

only at the highest dose.
The agent was absorbed rapidly, with
peak blood levels generally achieved 1–4 hr 8
after dosing. The half-life of the parent sub-
stance ranged from 0.8 to 4.5 hr. Although
we could not accurately determine the 6
AUC0–12 hr on day 4 for the lower dose and
hence the ratio of AUC 0–12 hr for the two
dose levels, the concentration–time data indi- 4
cate a dose-dependent increase in blood con-
centrations within this dose range. For the
higher dose, the ratio of AUC0–12 hr on day 2
4/AUC0–∞ on day 1 was approximately 1:3,
suggesting accumulation of the parent sub-
stance; however, the high degree of inter- 0
individual variability makes these comparisons 0 2 4 6 8 10 12 14 16 18 20 22 24

relatively imprecise. Time (hr)

The fenitrooxon metabolite appeared
Figure 1. Fenitrothion plasma concentrations (mean, standard error) after 0.36 mg/kg/day (dose 2). The rise
to co-elute with a large caffeine peak, in fenitrothion concentration at 16 hr postdose on dose 2 day 1 is due to administration of the evening dose
which prevented determination of its blood at 12 hr postdose; this measurement reflects fenitrothion levels 16 hr after the initial (morning) dose plus
concentrations. 4 hr after the evening dose.

Table 2. Fenitrothion plasma concentrations (ng/mL): dose 2 (0.36 mg/kg/day fenitrothion).

Time (hours postdose)
Subject 0 0.5 1 2 3 4 6 8 10 12 16 24 D/L
Day 1
001 a a a 0.89 0.30 0.20 a a a a 0.59 a 0.20
002 a 1.13 1.36 0.82 0.35 0.70 a 0.22 a a 2.05 0.35 0.10
003 a a a a a 0.43 a a a a 0.42 a 0.40
004 a 16.10 15.28 5.15 1.82 1.16 1.07 0.67 0.31 0.47 2.32 0.91 0.10
005 a 0.33 0.85 0.60 1.46 0.68 a a a a 0.27 a 0.20
006 a a 0.40 0.62 a a a a a a 0.40 a 0.20
007 a 0.24 0.33 1.30 0.71 0.53 0.47 0.28 0.26 a 1.79 0.34 0.10
008 0.34 0.13 1.45 1.70 1.78 1.20 0.40 0.44 0.39 0.95 3.70 0.56 0.20
009 a 0.22 0.17 0.72 0.56 0.58 0.31 0.18 a a 0.54 0.17 0.10
010 a 0.37 0.17 a a a a a 0.55 a a a 0.10
011 a a a a 0.62 a a a a a 0.61 a 0.40
012 a a a a a 0.28 a a a a 0.50 a 0.20
Day 4
001 a 0.29 1.43 4.44 2.75 2.00 0.71 0.32 0.42 a a a 0.20
002 0.24 1.05 16.40 3.66 1.82 1.36 1.90 0.82 0.35 0.28 0.19 0.22 0.10
003 0.52 1.15 1.30 2.08 1.58 2.50 1.08 1.40 1.04 0.53 0.51 0.45 0.40
004 1.58 b 22.68 10.13 7.64 6.97 2.82 2.24 1.99 1.66 1.74 1.07 0.10
005 0.34 6.30 5.70 6.20 7.51 2.37 a 0.88 a a 0.34 a 0.20
006 a 6.44 10.24 4.31 1.96 1.18 0.73 a a 0.62 a a 0.20
007 0.51 1.17 1.30 3.60 1.44 0.96 2.28 1.37 0.89 0.96 0.65 0.39 0.10
008 0.80 3.22 23.68 8.26 5.61 3.61 1.86 1.61 1.61 1.36 0.83 0.52 0.20
009 a 4.69 4.15 1.96 1.23 0.56 0.22 a a a a a 0.10
010 a 1.24 1.61 0.12 a a a a a a a a 0.10
011 a a a 1.15 0.56 0.65 a a a a a a 0.40
012 0.44 0.96 3.51 2.34 2.66 1.49 a a 0.49 a a a 0.20
For calculating the means, half the D/L value was assigned for first value D/L level, then zero for subsequent values.
aNot detected. bNo sample was obtained.

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Articles | Meaklim et al.

Table 3. Pharmacokinetic parameters of fenitrothion: dose 2 (0.36 mg/kg/day). acetylcholinesterase inhibition, there has also
Cmax (ng/mL)a Tmax (hr)a AUC (ng/hr/mL)a t1/2 (hr)a been some concern about the endocrine and
reproductive toxicity, or more specifically, the
Day 1 2.2 ± 4.4 2.5 10.2 ± 12.0 2.5 ± 1.3
inhibitory effects on the human androgen
Day 4 8.5 ± 8.1 1.0 30.9 ± 21.5 3.6 ± 4.0
receptor (9). A recent study using HepG2
aValues derived by averaging individual measurements of subjects with sufficient levels to enable calculation of the relevant
human hepatoma cells and male Sprague-
parameters.
Dawley rats has demonstrated that fenitroth-
ion competitively antagonizes androgen
Table 4. Excretion of MNP metabolite related to fenitrothion dose.
receptor activity in transfected cells and causes
Dose 1 Dose 2 regression of androgen-dependent tissue
Day 1 Day 4 Day 1 Day 4 weights in vivo (9). Researchers reported that
Mean MNP excretion (mg) 5.97 3.63 9.85 5.69 inhibition of androgen receptor function in
Fenitrothion equivalent (mg) 10.8 6.56a 17.8 10.3a vivo occurred at a dose of fenitrothion that did
Mean oral fenitrothion dose (mg) 13 6.75 26.4 13.5
Percent excreted in 24 hr 83 97 67 76
not significantly alter acetylcholinesterase activ-
ity. These findings have not resulted in a
aOnly the morning fenitrothion dose was given to subjects on day 4. decrease in the ADI and were not considered
in this study, where we based the safety of feni-
was depressed in a clinically significant fashion was considered sufficient to produce steady- trothion on its inhibition of cholinesterase.
(i.e., more than 25% depression from base- state blood concentrations close to those likely In summary, these results suggest feni-
line). The largest decrease in red blood cell after a more prolonged period of dosing. trothion is rapidly absorbed and extensively
cholinesterase activity from baseline was 17% Results of the toxicokinetic study indicate metabolized after oral administration to
during dose 1 and 12% during dose 2. Most fenitrothion is rapidly absorbed and extensively humans. The lack of significant suppression of
subjects showed less than a 10% decrease in metabolized in humans. The majority of each plasma or red cell cholinesterase (and the
red blood cell cholinesterase activity. Changes dose was rapidly excreted in the form of MNP. absence of symptoms or of abnormalities in
in plasma cholinesterase activity were variable, However, the AUC observed after 3 days of laboratory testing) after 3 days of dosing at a
with subjects demonstrating an increase, dosing was approximately 3-fold greater than level 72 × that of the ADI suggests the present
decrease, or no effect after fenitrothion dosing. that seen after the initial dose, raising the pos- ADI confers a substantial margin of safety, at
Toxicity monitoring. No clinically signifi- sibility that excretion is less rapid after the least in relation to acute (first dose) and suba-
cant changes were noticed in blood pressure or initial dose. Further studies with a longer cute effects of the agent. However, more pro-
pulse rate. No abnormalities were observed duration of kinetic monitoring would be longed repeat-dosing studies are required to
among the individual hematologic and bio- needed to determine whether significant resolve the issue of accumulation.
chemical parameters monitored, and no trends pharmacokinetic accumulation is occurring.
were observed in mean values. Few symptoms The findings of rapid absorption and exten- REFERENCES AND NOTES
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308 VOLUME 111 | NUMBER 3 | March 2003 • Environmental Health Perspectives