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| November 22, 2002 Page 1 of 5 PIRIB/M.Howard
November 22, 2002
Public Information and Records Integrity Branch (PIRIB)
Information Resources and Services Division (7502C)
Office of Pesticide Programs (OPP)
Environmental Protection Agency
1200 Pennsylvania Avenue, NW
Washington, DC 20640
Re: Docket ID Number OPP-2002-0202
Lindane Reregistration Eligibility Decision (RED)
The purpose of this letter is to comment on the EPA’s Lindane Reregistration Eligibility
Decision (RED), which was made available for public comment on September 23, 2002.
The National Pediculosis Association®, Inc. (NPA) is a non-profit organization serving
the public since 1983 and dedicated to protecting children from the misuse and abuse of
potentially harmful lice and scabies pesticidal treatments.
The NPA urges the EPA to recognize the risks associated with the pharmaceutical use of
lindane for the treatment of lice and scabies as part of the Agency’s RED document.
Consideration of the risks of pharmaceutical use of lindane is appropriate because the
risks apply not only to the child or individual being treated, but also to the caregiver
(“applicator”), the public at large and the environment.
The extent of exposure to lindane from pharmaceutical use is quite large. According to
the National Prescription Audit, 270,000 prescriptions for 1% lindane lotions and
641,000 prescriptions for 1% lindane shampoos were filled in 2001 for the treatment of
scabies and lice, respectively. These numbers alone account for 0.35% of the U.S.
population. However, lindane is also purchased in bulk quantities for treatment, as well
as prophylaxis, for head lice, pubic lice, body lice and scabies in nursing homes,
hospitals, jails, and shelters where it is common practice to treat not only residents but
also contacts and staff. In addition, residential use of lindane can involve entire families
and contacts (baby sitters, relatives and guests) when only one family member has
symptoms of an infestation. Therefore, it is more likely that closer to 1% of the United
States population (2-3 million individuals) is exposed to lindane in shampoos and lotions
on an annual basis. This extensive pharmaceutical use, according to the EPA’s own
marketing research (EPA memorandum “Estimated concentrations of Lindane in surface
water used as a source of drinking water from use and disposal of shampoo and lotion
into household wastewater” April 25, 2002) amounted to 1914.6 kilograms (over two November 22, 2002 Page 2 of 5 PIRIB/M.Howard
tons) during 1999-2000, most of which ended up being flushed down the drain,
contributing to pollution of the environment and our nation’s waters.
The NPA is concerned that the Agency’s Lindane Reregistration Eligibility Decision
only considered toxicology studies provided by lindane manufacturers in setting
exposure limits.
Lindane is a neurotoxin. In setting acute oral exposure limits in the Lindane RED
document, the EPA used results from an acute neurotoxicity screening battery in rats
(MRID #44769201–1999; see EPA memorandum “Revised HED Risk Assessment for
Lindane” July 31, 2002), where the No Observed Adverse Effect Level (NOAEL) was 6
mg/kg/day (females) and the Lowest Observed Adverse Effect Level (LOAEL), based on
increased grip strength and decreased motor activity, was 20 mg/kg/day (females).
In contrast, the Agency for Toxic Substances and Drug Registration (ATSDR) used a
published study by Joy et al. (1982) to set acute oral exposure limits in their assessment
of lindane (ATSDR’s July 1999 report entitled “Toxicological Profile for Alpha-, Beta-,
Gamma- and Delta-Hexachlorocyclohexane”). The study by Joy et al. examined kindling
(the development of seizure with repeated application of initial subthreshold electrical
stimuli) in rats, and reported a NOAEL of 1 mg/kg/day (males) and a LOAEL of 3
mg/kg/day.
The choice of the acute toxicology study used to set the NOAEL for lindane impacts the
risk assessment for pharmaceutical use of lindane to treat lice and scabies. In the
Lindane RED, the Agency uses a Margin of Exposure (MOE) approach to assess risk to
humans, where the margin of exposure is the ratio of the NOAEL in acute toxicity studies
to the actual exposure in humans. Margin of Exposure data for 1% lindane lotion is
presented in Text Table 1. The MOE target is 100. When the study by Joy et al (1982)
is used to set the NOAEL, the MOE for the pharmaceutical use of lindane is
between 0.7 and 2, on average 100 fold less than the desired safety margin for a
product that has effective, alternative therapies on the market.
Text Table 1: Risk assessment for use of 1% lindane lotions for treatment of scabies.
MOE MOE Dose*
(mg)
Age Group
(using ATSDR’s
NOAEL = 1
mg/kg/day)
(using EPA’s
NOAEL = 6
mg/kg/day)
Body
Weight*
(kg)
Equivalent Oral
Exposure
(mg/kg/day,
assuming 10%
absorption)
1
2
0.91
1.4
0.67
1.3
6
12
5.5
8.6
4
7.5
600
300
250
150
200
100
60
60
22
22
13
13
Young Adult
Young Adult
Child (4-6 yrs)
Child (4-6 yrs)
Toddler (1-3 yrs)
Toddler (1-3 yrs)
1.0
0.5
1.1
0.7
1.5
0.8
*Values of Body Weight and Dose are taken from the EPA memorandum of 7/31/02 “Revised Assessment
of Risk from Use of Lindane for Treatment of Lice and Scabies.”
The EPA and FDA both acknowledge that there is insufficient safety data following use
of 1% lotions. The FDA has made labeling changes to address this issue. November 22, 2002 Page 3 of 5 PIRIB/M.Howard
The NPA takes exception to the EPA’s anticipation that pending label changes that
restrict use to patients who have attained adult stature will eliminate risks to young
children. The underlying assumption is that the consumer will use the product in
accordance with the revised label. More likely, the consumer will follow the common
practice of treating everyone in the affected household (including children under 60 kg)
with the product.
The NPA is also concerned that the EPA doesn’t acknowledge that the proposed
FDA changes in the label for lotions containing 1% lindane will not eliminate the
risks to young adults. Studies of lindane as an anthelmintic for humans (summarized in
the Handbook of Pesticide Toxicology, Academic Press, Wayland J. Hayes Jr. and
Edward R. Laws, Jr., editors, 1991, Volume 2, p.805) suggest that ingestion of as little as
0.64 mg/kg/day x 3 days can lead to poisoning and convulsions in humans. Even with
the revised labeling, young adults will have a MOE of less than six, which is an
inadequate safety margin to ensure minimum risk of toxicity from lindane after
application of the lotion.
In addition, the NPA takes exception to the Agency’s conclusion that lindane
pharmaceutical products used for treatment of lice (1% lindane shampoos) do not
pose acute human health risks when used in accordance with directions provided on
the label. The Agency based their conclusions on a comparison of mean peak blood
levels following the use of Kwell® shampoo (maximum individual value 0.00613
micrograms/mL) and the peak blood level of 0.32 micrograms/mL reported for a single
case of acute accidental ingestion which resulted in short-term adverse effects. The NPA
respectfully suggests that the Agency consider the maximum blood levels following 1%
lindane shampoo treatment when compared to those attained following 1% lindane lotion
application (0.00613 micrograms/mL and 0.064 micrograms/mL, respectively) for their
analysis. This data suggests 1% of the lindane in the shampoo is absorbed through the
skin. The equivalent oral exposure from the shampoo (assuming 1% absorption) is
approximately 0.1 mg/kg/day (see Text Table 2). If the ATSDR NOAEL is used for
risk assessment, this analysis suggests that the amount of lindane absorbed from the
shampoo is approximately 10 times the amount that would provide a MOE of 100.
Text Table 2: Risk assessment for use of 1% lindane shampoo for treatment of lice.
MOE MOE Dose*
(mg)
Age Group
Body
Weight*
(kg)
(using ATSDR’s
NOAEL = 1
mg/kg/day)
(using EPA’s
NOAEL = 6
mg/kg/day)
Equivalent Oral
Exposure
(mg/kg/day,
assuming 1%
absorption)
60
120
10
20
9.1
14
6.7
0.1
0.05
0.11
0.07
0.15
600
300
250
150
200
60
60
22
22
13
Young Adult
Young Adult
Child (4-6 yrs)
Child (4-6 yrs)
Toddler (1-3 yrs)
55
86
40
Toddler (1-3 yrs) 13 100 0.08 75 13
*Values of Body Weight and Dose are taken from the EPA memorandum of 7/31/02 “Revised Assessment
of Risk from Use of Lindane for Treatment of Lice and Scabies.”
November 22, 2002 Page 4 of 5 PIRIB/M.Howard
In the U.S., the NPA received, within a two- year period, over 1100 reports of the harmful
side effects of head lice and scabies treatments containing pesticides; 500 of these reports
related specifically to lindane preparations, most commonly known as Kwell®. It is
generally accepted there is significant under-reporting of adverse effects. The NPA’s data
would support this and testifies to reporting as one of the most serious weaknesses in fair
assessment of risk to the environment and human health. A single application of
Kwell® to nineteen geriatric inpatients because of an outbreak of scabies resulted in
seizures in three of them (Tenenbein, M., 1990.Vet. Hum. Toxicol. 32:363).
The NPA urges the EPA not to overlook the shampoo as a health concern, particularly
since there are other, safer treatments that are effective for lice. For exa mple, the FDA
has approved medical devices for combing that provide cost effective, ecological, self
sufficient and a feasible technique for the diagnosis and treatment of head lice
(DeMaeseneer, J. et al. 2000. BMJ. 321.1187). Populations such as children, the elderly,
and pregnant or nursing mothers, who are at higher risk of having adverse effects to
lindane shampoo, should be encouraged to use combing as the method of choice in the
treatment of head lice infestations. Combing has the additional benefit of preventing the
predictable development of lice resistance that comes with pesticide reliance alone. An
emphasis on safer alternatives is consistent with legal requirements outlined in the
Massachusetts Commonwealth Chapter 85 Acts of 2000 to take eve ry available
opportunity to protect children from pesticides in school and childcare settings. The NPA
urges the EPA to take a similar stance in the Agency’s Lindane RED and emphasize the
strong preference to avoid using lindane pharmaceuticals when possib le.
Finally, the NPA is also concerned about the impact of pharmaceutical use on
pollution to the environment. According to the Agency’s own memorandum (dated
April 25, 2002), over two tons of lindane are used pharmaceutically for the treatment of
scabies and head lice, most of which ends up down the drain and contributing to chronic
exposure levels in water and the food chain. The Agency argued, on the basis of their
risk assessment, that the chronic exposure to lindane in the diet is not a concern because
exposure estimates were significantly below the agencies assessment of the chronic
Population Adjusted Dose (cPAD) that would present a dietary risk to man. The Agency
used a NOAEL of 0.47 mg/kg/day based on a chronic dietary feeding study in rats whe re
the lowest observed adverse effect level (LOAEL) for periacinar hepatocyte hypertrophy,
increased liver and spleen weights, and decreased platelets was 4.8 mg/kg/day. The
Agency then calculated the cPAD by multiplying the NOAEL by 100, the uncertainty
factor (UF: 10X for inter-species variation and 10X for intra-species variation) and again
by 3, the Food Quality Protection Act Safety Factor (FQPA SF). The Agency did not
consider any studies evaluating the effects of lindane on immunological function in their
toxicological assessment. In contrast, ASTDR did consider immunological effects and
set the minimum risk level at 0.000012 mg/kg/day based a study where the LOAEL for
changes in cell-and humoral-mediated immune function in mice was 0.012 mg/kg/day
and serious adverse effects (necrosis of the thymus) were observed at 1.2 mg/kg/day
(Meera et al., 1992).
November 22, 2002 Page 5 of 5 PIRIB/M.Howard
The choice of study for setting the cPAD has profound consequences in terms of
calculating the health risk of consuming lindane in the food supply. As illustrated in Text
Table 3, the Agency’s decision to use chronic hepatic toxicity as an end-point results in
the conclusion that the amount of lindane currently in the diet poses no health risk to
humans. If the Agency were to have considered immunological function as an end-point,
as did ASTDR, their conclusion would have been very different.
Text Table 3. Impact of choice of chronic toxicity study for determining cPAD for
lindane exposure on estimated dietary risk to man.
ATSDR EPA Chronic
Exposure*
Population
Subgroup
LOAEL = 0.012 mg/kg/day
UF = 100; FQPA SF =10
cPAD = 0.000012 mg/kg/day
NOAEL = 0.47 mg/kg/day
UF = 100; FQPA SF = 3
cPAD = 0.0016 mg/kg/day (mg/kg/day)
% cPAD
450
600
1442
% cPAD
3
5
11
U.S. Population 0.000054
All infants (<1 yr) 0.000072
Children (1-6 yrs) 0.000173
*Taken from the Agency’s Lindane RED
The NPA urges the Agency to reconsider the toxicology studies of the Lindane
Reregistration Eligibility Decision (RED) and to include the ATSDR criteria and all
other available scientific data in order to obtain the most thorough assessment and
to provide for the greatest margin of safety to protect the public and the
environment.
Respectfully submitted,
Deborah Z. Altschuler
President
National Pediculosis Association
50 Kearney Road
Needham, MA 02494
The National Pediculosis Association acknowledges BethAnn Friedman Ph.D.,
Arlington, MA for her assistance in preparing this document.
(signature on document submitted with original) |
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