“If a huge skull and crossbones were suspended above the insecticide department the customer might at least enter it with the respect normally accorded death-dealing materials.” —Rachel Carson, Silent Spring
Rex: beset with the furrowed brow of vex...
Part One: Learning Curve
Many of today's synthetic insecticides (“noxious organism control agents”) are powerful poisons that had their origin in the development of chemical warfare agents (neurotoxins), and are classified as carcinogens (cancer causing)
by the EPA.
Organophosphates (OPs) and carbamates are common synthetic pesticides found in flea & tick killers. Both are nerve-paralyzing agents capable of causing convulsions, nausea and respiratory arrest: not only in the insects they are intended to obliterate, but in the host animal (your dog) as well. Research spanning decades classifies many as mutagents (causing genetic damage), as well as hormone and immune system disrupters.
The peak flea and tick season invariably results in many cases of pesticide-related poisoning of not only the targeted dog or cat, but often also, children and other pets who touch them. Paradoxically, application instructions on certain products direct you to vigorously rub powders deep into your dog’s coat, or soak a flea-infected dog thoroughly with a bottled or spray formula… while in parallel, warning of the hazards to humans. Often, the admonishment is “do not pet” your dog for 24 hours, and even to keep multiple dogs separated during that period. Under what circumstances would you take your child to a facility for a bath in poison, (such as we do when a "flea dip" is advocated?) Insecticidal powders (including dispersions from flea or tick collars) can be inhaled or licked off by your dog; and especially in liquid formulations, these chemicals are intended to be absorbed through his skin and attach to blood plasma: and thereby circulate through his entire body. This systemic mode of application may, depending upon factors of individual sensitivity, set the stage for a myriad of adverse effects, including possible genetic damage and vital organ failure.
Aside from immediate toxicity, many researchers link the rise in cancer seen in companion animals and residual chemical persistence in the environment to the use of chemical pesticides against fleas and ticks. For that reason, even in the midst of an insect invasion, it's important not to let the urgency of your need to get rid of the pests override the risk factors for your dog, other pets, and the household; nor, to be complacent about the pervasive environmental issues raised by use of these products, which the National Resources Defense Council describes as “rash and unnecessary.”
Boscoe & Clifford: Who's just arrived?
The Mythology of “Safety”:
How We Use the Benefit vs. Risk Standard
It is unwise to assume that because a product is available at the grocery store, that it has been tested for safety. Nor should you take this assumption regarding a “professional” pest control applicator, or even products recommended
by your veterinarian.
The 1947 law regulating pesticides—the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) ( [P.L. 75-717] 7 USC § 136 et.seq.)—is based on a benefit-risk standard, and does not use safety as the fundamental basis for permitting a pesticide on the market. This allows pesticides to be used even if they pose hazards to humans and the environment,so long as the benefits outweigh the hazards: any health or environmental threat can be acceptable if the estimated economic benefits are large.
FIFRA has been amended many times, most recently through the 1996 Food Quality Protection Act; however, imposed deadlines have not been met, some registered pesticides do not meet current testing standards, and the EPA has little information about the cumulative impact of multiple organophosphates or of other similarly functioning chemicals.
Marnie: indefatiquable charm
“Active” vs. “Inert” Ingredients:
What's the Difference? To evaluate the risks associated with any of these products, it is important to understand that flea & tick pesticides are made up of more than one chemical: composed of“active” ingredient(s), whose identity must be listed on the label (percentage by weight); and“inert” ingredientswhich do not have to be disclosed.
FIFRA allows manufacturers confidentiality on issues they claim would otherwise make them vulnerable to market competition. As such, “inert” ingredients became protected by industry as “trade secrets.” 60 years on, however, it is clear that the act protects commerce, yet supersedes the public’s right to know to about many chemical formulations, and thus impedes the consumer’s awareness of health hazards resulting from exposure to un-named chemicals. Without full disclosure, the consumer is unable to make educated decisions as to which chemicals to avoid. Contemplating concepts of consumer rights and manufacturer liability exposure, it is troubling to remember that legally, dogs are considered “property,” and therefore limited in value to
“cost of purchase.”
While the word “inert”
suggests benign effect
(and likely connotes “safety” to the consumer), this is misleading, because these undisclosed ingredients may not be biologically, chemically, or toxicologically inactive: legally, “inert” merely means those substances that are not the “active”
From a marketing perspective, consumers may feel comforted by the concept that a product contains only a minuscule amount of an “active” ingredient, and up to 99.9 percent “inert” ingredients, suggesting they are inactive: probably only carriers, conditioners, (excipients) etc. The reality should be opposite, however: because testing required for Environmental Protection Agency(EPA) registration is rigorous only for the “active” ingredients, whose toxicological profiles must be disclosed on inserts and packaging. Not so, for the “inert” ingredients, generally tested in short-term studies for acute (immediate) toxicity only. Moreover, the cumulative and synergistic effectsof these chemicals (the interaction of chemicals that when combined produce a total effect that is greater than the sum of the individual chemicals), are not required to be tested for safety.
In actuality, many “inert” ingredients are as toxic, or more toxic, than the registered “active” ingredients. In 1987, EPA “requested” registrants of pesticide products to voluntarily substitute the term “other ingredients” in lieu of the term “inert ingredients” on the label. According to the EPA’s Review of 2008 Incident Reports for Spot-on Insecticides: “These ingredients may have been responsible for a number of the (adverse) incidents as some have toxic properties…”In the current marketplace, neither the consumer or his veterinarian has means to gain knowledge about what these ingredients might be, and expectations about safety must be conditioned on that basis.
Teddy: "Who's just arrived?"
So... What’s the
Pri¢e of$afety? US consumers expect that products on store shelves have been vetted (registered) by the EPA’s Pesticide Division for safety before marketing. But how (or if?) is this accomplished?
(POISON) TESTINGis done on healthy “domestic animals” (mice, rats, dogs and cats) to confirm the median lethal dose or LD50: the dose at which the product would poison/kill 50 percent of a of a test population after a specified test duration, in order to determine acute (not chronic) effects. Generally without anesthesia or other medication (under the assumption that “relief” from pain or nausea/gastrointestinal distress would alter test results), animals are force-fed (oral LD50), injected into tissues or “body cavities” (injectable LD50), wiped (dermal LD50), or clamped with masks (inhalation LD50). Similar measures include LC50 (Lethal Concentration, 50%) or LCt50 (Lethal Concentration & Time, 50%), also known as Haber's Law: a mathematical statement of the relationship between the concentration of a poisonous gas and how long the gas must be breathed to produce death, or other toxic effect. The heavily criticized LD process may substitute the modernized “Up and Down Procedure,” in which fewer test animals are dosed singly and the dosage of consecutive animals is increased or decreased based on the survival of the previous animal.
A “clinical/health assessment” (a checklist designed to quantify and standardize symptoms) using a “rubric” scoring guide is used to determine the highest experimental point that is without adverse effect, called the No Observed Adverse Effect Level (NOAEL). NOAEL is used to support establishing a dose-response relationship as part of risk assessment for regulatory approval, and as such, serves as the basis for EPA “safety” level, or “reference dose.” The results are mathematically extrapolated to make judgments regarding general consumer application, and adjusted for weight of the dog, although the very generalized nature of the process may make that figure unreliable. During and following the study, certain surviving animals are killed in order to review identifiable system damage to vital organs (lungs, kidneys, etc.).
Humphrey: Scottish Cammo-man...
It's important to understand that veterinary professionals (as well as insurance companies and legal experts) identify and define adverse effect according to “clinical symptoms” that are “observable.” That is: signs that are strictly visible (evident because they can be seen) to the study team, or, otherwise identified in some other tangential way. Thus, it is only “acute” adverse reaction that would be noted during the research process.
This imbedded limit on “scientific” definition constrains the framework of how veterinary drugs are evaluated, submitted for regulatory approval, and marketed: since “sub-acute” (systemic, or internal) reactions are not identified as relevant in any way. Although the ability of a dog to tolerate a powerful insecticide or drug depends on his total immune response—which can be influenced by a myriad of factors, including heredity, general health, as well as environmental, food, or stress pressures—that is only relevant to the extent that an adverse reaction would manifest both swiftly and visibly.
Lulu: a courser's gaze
ACUTE and RAPID ONSET DISEASE
TESTS (skin “corrosivity” and inflammation reactions, the eye-irritancy “Draize” test, nervous system effects) can reveal issues in a comparatively short time period. These studies are conducted for 3 to 26-week intervals, using exaggerated dosages to compensate for the short testing periods. While health effects resulting from high doses of the chemicals are relevant, they do not reveal possiblechronic effects (examples: cancer, developmental or reproductive damage, DNA damage, immune system suppression) that may take months or years to manifest. Commonly also unaccounted for, is individual, sex, and breed sensitivity: a minimal “impact dose” for one animal could be lethal to another, even adjusted for weight; small and other so-called high-strung breeds or females are particularly susceptible to neurotoxin adverse side-effects.
Long-term testing is not generally undertaken, as it is ordinarily not required for regulatory approval, and as such, the cumulative effect of pesticide use over the lifetime of the dog is simply not known from product development research. Further, the EPA does not require testing for the synergistic effect of the combined influence of chemical exposure and outdoor environments (not replicable in the laboratory). In the final analysis, we are failing to acknowledge and question that, essentially, it is the dog himself who becomes a living chemical research vessel of insecticide over his lifetime.
Remember that pursuant to FIFRA, the EPA registers pesticides on a COST-versus-BENEFIT BASIS: weighing health and environmental concerns against the economic gain/benefit to the manufacturer and the end user of the product. As such, this “risk-benefit balancing analysis”represents an especially significant relationship to “over the counter” (OTC) treatments, which may cost less than half of a veterinary supplied product.
Currently, no pre-market clinical trials (studies on pets in a “real world” environment, before the product goes on the market) are required for EPA approval, and the confined, short-term tests are often only on one breed of dog, limiting the veracity of predicted effects across a broader population of users. According to the National Research Defense Council, the EPA’s “risk assessments have been handicapped by flawed and inconsistent assumptions that understate the risk from pet products,”and which do not adequately account for environmental issues of pesticide bio-accumulation, bioconcentration and pesticide biomagnification. In fact, in the summary of meetings between the EPA and manufacturers (click here for PDF), EPA investigators found that the data the EPA now requires for registration do not accurately predict the toxicity when the product is approved and being widely used by consumers.
Honey: locked onto a gull, beckoning overhead
Traveling protection: “Spot-ons.” As a profitable sales strategy, manufacturers drive the concept of insect killer/repellants that “travel” with the dog as a convenient response to the busy lifestyle of the modern consumer. These “spot-applied” synthetic, chemical-based insecticides bear names (developed through market research) that suggest protection and safety (Guardian®, Advantage®, Frontline®, Advantix®, Interceptor®, and others). But few consumers have a reasonable understanding of how these products work, that the toxic ingredients enter their dog’s internal filtering organs (liver and kidneys), move through his intestinal tract (where 80% of his immune system resides), and are eventually eliminated in his feces and urine
into the environment.
The oil-based drops are placed between the dog’s shoulder-blades to prevent him from licking it off. A common (off patent) ingredient is imidacloprid (Bayer’s Advantage®), a nicotine-based (chloro-nicotinyl) insecticide (1994), belonging to a class of chemicals called neonicotinoids. These chemicals act as a neurotoxin and interfere with the transmission of nerve impulses in insects by binding to certain nicotinic acetylcholine receptors, causing paralysis and death. Neonicotinoids are selectively more toxic to insects than warm-blooded mammals, because they block a specific neural pathway that is more abundant in insects; hence their efficacy as synthetic broad-use insecticides, particularly in lage-scale agricultural applications. However, the French Minister of Agriculture suspended the use of imidacloprid as a treatment for sunflower seeds (1999) and corn (2004) owing to studies linking it to collapse of honeybee populations. Other European regulatory agencies have likewise suspended use of similar systemic neonicotinoid pesticides for this reason.
Marcey: turning an elegant shoe
What does the term “Systemic” Mean?
Using vague and contradictory terminology, manufacturers imply that these chemicals are not absorbed into the dog’s system, but remain on the surface of the skin.
As an example, Merial Limited states that Frontline® (a phenylprazole insecticide) is “not systemically active,”but describes translocation (a change in location): that Frontline® is “gradually dispersed by the pet's natural oils, collecting in the oil glands in the skin… then wicked onto the hair over the next 30 days” (diffusion and capillary action; transfer from hair to hair as the dog moves);
and “...Frontline® will not go into the bloodstream and hence very safe...” But this suggests an illogical conclusion: that fipronil (the “active” ingredient) remains in the sebaceous (oil) glands beneath the skin— and then leaves through the same entry point (to the hair) without moving into any other part of the dog’s body.
However, a 1996 EPA memorandum, “Review of Domestic Animal Safety Studies,” cites a study: “in which radio-labeled fipronil was administered to dogs… demonstrat(ing) that the chemical is absorbed systemically. Plasma (intravascular fluid containing blood cells) levels of radioactivity were detected from day 2 to day 30 post-treatment.” Regarding packaging, the EPA concluded: “These statements (that “Fipronil is not absorbed into the body”) should be deleted from the label”(click to view PDF). Fipronel has been linked to onset of “aggressive” behavior in adult dogs, and the EPA classifies fipronil as a carcinogen because exposure to fipronil caused malignant thyroid tumors in laboratory animals.
Herb: on the qui vive
When fipronil is exposed to light it can break down (photo-degeneration) into a smaller molecule called MB4651324 or fipronil-desulfinyl, which because of its size, can penetrate skin more readily. Based on acute toxicity testing sponsored by the manufacturer, a 1998 EPA Health Effects Division risk assessment estimated that MB4651324 is nearly 10 times more toxic than fipronil itself.
EPA identifies fipronil as highly toxic to certain birds and fish (1996), and UK researchers (2003) identified its “half life” persistence in soils up to 7 months. Scientists at Murray State University (KY: 2002) found that during the first month after treatment, petting an animal transferred fipronil from the animal to the person. And remember, the chemicals in Frontline are supposedly among the “more safe group of spot-ons.”
Fipronil was developed between 1985 and 1987 by Rhone Paulenc AG as a broad-use insecticide, market-introduced in 1993. The National Pesticide Information Center (NPIC) describes that it has since been integrated into a wide variety of products including “pesticide products, granular products for grass, gel baits, spot-on pet care products, liquid termite control products, and products for agriculture.”
Although Zoetis Inc. does describe that its prescription spot-on Revolution® (generic: Selamectin; heartworm, fleas, ticks, mites) “enters the bloodstream through the skin,” the term “systemic” is quietly sidestepped. Zoetis also declares that “Revolution® is a prescription-only medication available only through a veterinarian, not a pesticide registered by the Environmental Protection Agency (EPA).”
SECRETS. The active ingredients in Frontline Plus® are Fipronil (9.8%) and S-methoprene (8.8%). Fipronil disrupts the normal nervous system functioning of insects by blocking the passage of chloride ions through the GABA receptor and glutamate-gated chloride (GluCl) channels, leading to hyper-excitation, paralysis, and death. This is how nerve gas works. In laboratory tests, fipronil was shown to cause kidney damage, and alteredlevels of sex and thyroid hormones, and thyroid lesions. Methoprene has shown leading to liver enlargement and kidney damage. As a classification, many spot-ons are associated with severe depression, lethargy, and symptoms concomitant with aggravated liver toxicity. Moreover, metabolites (breakdown of the chemical into new chemical compounds during the metabolism process in the body) of imidacloprid may in fact be more toxic than the imidacloprid itself.
S-methoprene is a biochemical insecticide and insect growth regulator that mimicks natural juvenile hormone of insects. Juvenile hormone must be absent for a pupa to molt to an adult, so methoprene treated larvae will be unable to successfully change from a pupa to the adult insect. This breaks the biological life cycle of the insect preventing recurring infestations.81.4% of the ingredients in this product are captioned as “inert” and as such, neither the consumer or his veterinarian has means to gain knowledge about what they are, or what their toxicological effects might be.
Bonnie: the eyes as windows to a gentle soul
REMEDIESthat lead to
ILLNESS and DEATH...? Over a recent 5-year period, at least 1,600 pet deaths related to spot-on treatments were reported to the EPA. In 2008 alone, the EPA recorded 600 deaths and 44,263 non-lethal complaints about spot-on flea & tick killing products. It’s not clear how many more consumers experienced issues, but did not file complaints with the
After revisiting the safety of these products the agency had previously approved, in March of 2010, EPA announced it will pursue changes in labeling to reduce consumer confusion, establish narrower weight ranges for per-vial dose of spot-ons, and “develop more stringent testing and evaluation requirements for both existing and new products.” The EPA also indicated that a review of “inert (undisclosed) ingredients” (regarded as industry trade secrets) was important, owing to the “toxic properties” and potential for interaction of some ingredients; (view PDF).
Unfortunately, these actions don't address the larger concerns about the roles of economics and politics play in cost/benefit evaluation and registration (pre-market approval) of these ectoparasiticides (antiparasitic drugs used to kill the parasites that live on the body surface). Based on EPA's analysis, not all of the pet poisonings can be explained by consumers misusing the products, and this brings into question the safety of the products themselves. Moreover, the review was narrow: other organophosphate and carbamate chemicals used in flea and tick collars, powders, sprays, and other products aren’t covered by the new protocols.
Leroy: a moment of wistful reflection...
The concentrations of pyrethroids (synthetic pesticides) in OTC spot-on products (example: Farnam Bio-Spot®,HartzUltraguard®) range from a 40% to an 85% solution: up to 17 times stronger than the toughest pyrethroid product currently approved for use on humans. Neither the Food and Drug Administration (FDA: regulating orally administered pet products), or the EPA, (regulating topically applied products), has registered a product for human application containing a pyrethroid concentration above 5%— and that FDA-approved product requires a doctor's prescription. EPA’s registration branch assumes that these high concentrations may be necessary because dogs (and cats) are more likely to come in contact with
fleas and ticks.
While the application instructions for Sergeant's Squeeze-on for Dogs directs the consumer to apply the treatment “to the dog's skin,” the warning section of that same label cautions: “Harmful if swallowed or absorbed throughskin,” (presumably human). According to a 2008 study published in The Veterinary Journal, dermal exposure by application to the skin or coat is the most common route of toxic exposure, potentially causing seizures leading to brain damage and death. The label ofHartz Ultraguard® Flea & Tick Dip for Dogs, a liquid intended for literally soaking a dog or cat in, cautions: “Environmental Hazards: Toxic to fish. Do not contaminate any body of water with this concentrate or dip.” Other Hartz spray-on products are labeled as toxic to aquatic invertebrates (animals without a backbone, such as insects, worms, mollusks, sea stars, jellyfish and others), and which represent food sources for avaian and coastal dwelling mammals.
Among the many controversies that Hartz Mountain Industries has been engulfed in, its Blockade®, an aerosol flea & tick spray backed by a multi-million dollar advertising campaign, was discontinued in 1987, after the company acknowledged that it had caused 366 animal deaths and 2,700 injuries; (as well as 56 human injuries). Hartz had been vigorously fighting negative press reports for years, during which time it added a precautionary wired-on tag to the cans as an interem step.
Lily: Can you spell "Supercalifragilisticexpialidocious" ?!
Reviewing the company’s LD50 and LC50 lethal toxicology studies, the EPA observed that Hartz’s methodologies were “inadequate to demonstrate the safety of the formulation,” and that since “the application rate of normal anticipated use” wasn't even specified, there was “no indication as to what margin of safety (was) present”;(click to view PDF). Eventually Hartz paid the EPA $45,000 to settle charges that they failed to report animal illnesses and deaths; EPA registration was cancelled in 1999.Subsequent replacement products seemed little more than reformulations.
In 2005, the EPA cancelled permission to use phenothrin in certain flea and tick products, at the request of Hartz itself.The products were linked to a range of adverse reactions, including hair loss, salivation, tremors, seizures, and numerous deaths in cats and kittens. Initially, the agreement called for new warning labels on the products. In March of 2006, the sale and distribution of Hartz's phenothrin-containing flea and tick products for cats was terminated. Consumer advocates complained that Hartz was clearly aware for years that the products were dangerous, and even once discontinued, they were not removed from retail shelves and persisted being sold, indefinitely. EPA's product cancellation order did not apply to Hartz flea and tick products for dogs, and Hartz continues to use phenothrin in a concentration of 85.7% in its Ultraguard® line of flea and tick
products for canines.
Jamie & Ozzie: anit-gravitational pull...
“The use of any product on the market to control fleas on pets is associated with a degree of hazard to the animal.” —Claude Kissin, Vice President, Hartz Mountain Corp., 1987
1987: Hartz Blockade® withdrawn from sale
after pet deaths. Today: Hartz Ultraguard® Collar for Dogs;
Active ingredient: Tetrachlorvinphos (14.55%) (classified a likely human carcinogen); Inert (undisclosed) ingredients, 84.43%.
Izzy: the artful observer
The Normal Dose as“Overdose”?
… Death as a “Side Effect”?
New generation flea & tick collars have more aggressive chemicals in the past, but all work by shedding microparticled (powdered) insecticides that your dog may inhale or consume through self-grooming. Among choices are Merck's Scalibor® Protector Band which uses a 4% concentration of Deltamethrin, a synthetic pyrethroid ester insecticide. The porous exoskeleton of fleas and ticks is susceptible to these axonic (nerve cell) toxins which hold open the sodium channels in the neuronal membranes (ordinarily, sodium ions pass through the membrane proteins, enter the axon, and propagate an “action potential”): unable to “de-excite,” the insect is paralyzed. Notable is that 96% of the ingredients in Scalibor® are inert (unidentified, protected industry “trade secrets”), and as such,neither the consumer or his veterinarian has means to gain knowledge about what they are, or what their toxicological effects might be.
Deltamethrin is neurotoxic to humans and has been found in human breast milk in areas of South Africa where pyrethroids are used for small-scale agriculture pest control. There are no antidotes, and treatment must be symptomatic. Extremely toxic to aquatic life (invertebrates cannot break down the neurotoxins), in small does, deltamethrin is eventually metabolized (biotransformation) and passed from the body of humans and vertebrate land animals, although toxicity has been observed in cattle (who were unable to stand), subsequent to agricultural preparations for
external application in tick control.
A competitor, Virbac Animal Health, asserts that its Preventic® Tick Collar for Dogs holds a higher efficacy rate, and also (as does the manufacturer of Frontline®), claims that it is “non-systemic.” The active ingredient, a 9% concentration of Amitraz(91% of the contents are inert), works in a similar manner to deltamethrin, and is used as a repellent, arachnicide (insecticide for arachnids), and pesticide synergist. Under the brand name Mitaban® and Preventic®, Amitraz is offered in liquid form for dilution into a veterinary or consumer-use dip to resolve infestation with the Demodex canis mite (mange), and as tick control for dogs. Because mammals have fewer of the specific neural pathways that these neurotoxins attack, they are considered “selective” to the insects when applied. The most common side-effect following this type of use is “in-coordination” and sedation of the dog... which can last up to 72 hours.
In 2006 the US Environmental Protection Agency classified Amitraz as a “Group C” (possible human carcinogic) carcinogen. Despite assurance that the collar “poses no significant risks to dogs or humans when used as directed,” Virbac cautions against extended close human interaction with the dog. Consumer packaging for Preventic® warns of possible canine allergic reaction, and a “Q&A” section answers questions about “overdose,” (although, it’s unclear how one could “overdose” use of a collar pursuant to affixing it around the dog’s neck as directed), forewarning to “seek emergency veterinary medical treatment” for symptoms that include “…in-coordination, slow heart rate, decreased body
temperature or death”
Cassie: the day is fading... happiness not!
Recent Introductions and
the meaning of “Market Value”
Ceva Animal Health introduced Vectra 3D® (AKA FirstShield™ and SimpleGuard®) in 2007, marketing the product additionally as a repellent, through veterinarians. Vectra adds dinotefuran (a newer neonicotinoid-class insecticide) to pyriproxyfen (see below) and permethrin. Unlike other spot-ons, application is run all the way from the dog’s tailbone to his collarbone. More than 58% of the product is “inert/other ingredients.” Vectra products are made by Summit VetPharm, originally a subsidiary of the Hartz Mountain Corp. (Summit was sold to CEVA Animal Health in 2010).
Bayer introduced Advantage® II and K9 Advantix® II “spot-on” topicals in January 2011: the active ingredient is pyriproxyfen (brand name: Nylar®), an insect growth regulator (IGR) that inhibits the development of eggs and larvae, helping to break the flea life cycle. Other IGRs include lufenuron (Novartis: Program® and Virbac: Sentinel®) and S-methoprene (Certifect®). Merial’s veterinarian-dispensed Certifect® was likely introduced as a result of their patent on Frontline® products expiring, adding amitrazto fipronil and S-methoprene.
Product introductions are also the result of fleas and ticks developing resistance and even immunity to the first generations of medications in some geographic areas. “Next gen” formulations (Advantage® II, Frontline® Plus) are stronger and more toxic to pests than their predecessors. Virbac Corporation’s Sentinel® Spectrum® (“the only 6 in 1 chew for parasites”: heart/round/hook/whip/tapeworms, fleas) adds praziquantel to the original milbemycin oxime/lufenuron pork-flavored monthly formula (also: Flavor Tabs®).
Merial Limited (Duluth, GA) introduced Frontline® Tritak™ for dogs in 2012, responding to the waning efficacy of Frontline® and Frontline® Plus reported in certain (generally humid) US states. Initially available in AL, FL, FA, LA, MI, NC, SC, TN and TX, it was rolled out nationwide beginning in 2013. Adding cyphenothrin (5.2%) to fipronil (9.8%) and (S)-methoprene (8.8%: the active ingredients in Frontline® Plus), Merial claims the stronger (“comprehensive… triple action”), 30-day formulation is waterproof and will begin killing adult fleas in 5 minutes; as well as ticks, flea eggs and larvae. Cyphenothrin is a broad spectrum synthetic pyrethroid insecticide that is generally effective against external parasites that have developed resistance to organophosphorous and carbamate insecticides: side effects are similar to permethrins (see discussion above). The product is contract-manufactured by Sergeant’s Pet Care Products, Inc., and distributed through veterinarians. 76.2% of the product is undisclosed: as “other ingredients.” Other spot-ons featuring cyphenothrin include: Fiprogauard Max, Sergeant's Silver Flea and Tick Squeeze-On Dog, Siproguard Max, Sentry’s Pro XFC, and Parastar Plus® (the brand name for the generic agent Fipronil mixed with cyphenothrin). In 2016, Merial added pyriproyfen (a pyridine-based pesticide introduced in 1996 to protect cotton crops against whitefly) as a flea hormone regulator to its original Frontline® formula (fipronil and (S)-methoprene) to create Frontline® Gold. Click here to read the EPA registration/review for cypehnothrin.
Murdoch: freewheeling innocence...
INSECTICIDES as a DOG TREAT?
Comfortis® (2007) and Trifexis® (Spinosyn class: also marketed as Vethical AcuGuard® and ComboGuard®) are pork-flavored chewable tablets dispensed by veterinarians, aggressively marketed as a convenient and cost-effective alternative to “spot-ons.” Consumable pest control “won't stain carpeting, upholstery or clothing.” Moreover, the tablets appeal to parents of small children: since there would be no transferable pesticide on the dog's fur: “Family friendly: no need to isolate… you can play with your dog immediately after treatment.” Both are produced by Elanco: the animal drug division of Eli Lilly and Co., and as drugs, these products fall under the purview of the US Food & Drug Administration.
Although Spinosyns work in a similar fashion to the isoxazolines, they kills fleas, but not ticks. Spinosyns activate reactions in the flea’s cellular ion channels (the nicotinic acetylcholine receptors or nAChRs), causing a fatal central nervous system reaction (involuntary muscle contractions and tremors resulting from activation of motor neurons) that leads to prostration, paralysis, and death. The selective toxicity of spinosad between insects and vertebrates may be conferred by the differential sensitivity of the insect versus vertebrate nAChRs.
The active ingredient is spinosad, a soil bacterium discovered to have pesticidal properties by Eli Lilly in the early 1980s. Partnering with Dow Chemical, the company developed spinosad for agricultural uses in the 1990s. The National Pesticide Information Center describes a study wherein dogs fed low doses of spinosad over a year showed “effects to [adrenal] gland and immune cells and increases in [certain plasma] proteins and fats.” Reported adverse effects have included pupil dilation, hypersalivation and hyperactivity, broad skin disorders, convulsions, stupor, blindness, depression, aggression,
paralysis, and death.
Trifexis® (Elanco, 2011: fleas, heartworm, intestinal worms) adds milbemycin oxime to spinosad. At least 965 canine deaths (some within hours of administering a first dose) have been reported to the FDA. Investigation is focusing on milbemycin oxime, being imported from China. Milbemycin oxime is the primary active ingredient in Sentinel® Spectrum® (Norvartis Animal Health US, 2011: milbemycin oxime/ lufenuron/ praziquantel). Other than reports similar to Elanco's earlier drug, a further 1,500 complaints are related to ataxia, (loss of muscle control: which had been added to the list of possible side effects in 2012). In a statement, the FDA indicated it is monitoring the “adverse reaction” reports—expecting they may be underreported—which may be cross-triggered by accompanying issues.
A veterinarian for the drug’s manufacturer, Elanco Animal Health, commented: “Everything we have on file is within expectations. We remain convinced that the value and benefit of this product still far exceeds the rare risk of these things happening, as unfortunate as they are… there is no certainty that the reported drug caused the adverse event… [there is] no established link between Trifexis use and death.”
Franz: dressed to the nines
Merk Animal Health introduced prescription Activyl® and Activyl® Tick Plus spot-on flea and tick control in 2012. The active ingredient is indoxacarb, an oxadiazine pesticide; the latter combined with permethrin. Inert ingredients comprise nearly 45% of the product.
In 2013, the FDA approved Merial’s (Frontline Vet Labs) NexGard™, a chewable prescription 30-day flea-tick control. The active ingredient is afoxolaner, a new classification isoxazoline-based compound (CBPI, an ectoparasiticide-insecticide/acaricide-flea adulticide: see Bravecto™, below) that inhibits subject ligand-gated chloride channels, in particular those gated by the neurotransmitter gamma-aminobutyric acid (GABA): this blocks pre- and post-synaptic transfer of chloride ions across cell membranes (chemical pathways where charged ions from dissolved salts (including sodium, potassium, calcium, and chloride) pass through otherwise impermeable cell membranes. Many physiological processes rely on these ion channels, which are gated to open and close in response to certain stimuli. Isoxazolines close the chemical gates on chloride channels, resulting in uncontrolled activity (hyperexcitation) of the central nervous system of susceptible insects, leading to death. As a systemic insecticide, fleas and ticks must attach and commence feeding in order to be exposed to the active substance (fleas: 8 hours; ticks: 48 hours).
Miranda: a coy and serene presence
By mid-2016, the FDA’s Center for Veterinary Medicine (CVM) had recorded 7,740 complaints of adverse reactions to Nexgard™, 2,048 of which were submitted in only six months between mid-June of 2015 and 06 January 2016; with a further 3,317 compiled by mid-October. May of 2017 saw the addition of a further 1,417 reports. The reports included, in order of frequency: vomiting, lethargy, skin reactions/dermatitis/erythema, seizures, panting, anorexia, (bloody) diarrhea, polydipsia (exessive thirst), loss of muscle coordination, fever, systemic endocrine and renal disorders, facial swelling, incontinence, anxiety, tachycardia, and death. Owing to limitations, the CVM database is likely incomplete: see discussion below.
Also in 2013, Bayer introduced its Seresto™ collar to the US. The active ingredients are 10% imidacloprid (chloronicotinyl compounds, used in greenhouses; 1996: Bayer’s Advantage®), and 4.5% flumethrin, (1986: α-cyano-pyrethroids ) an acaricide that repels and kill members of the arachnid subclass Acari, which includes ticks and mites, that has been used in Europe. 85.5% of the ingredients are classified as “inert,” or unidentified trade secrets.
The collar is a polymer matrix composition (polymerization is a process of reacting monomer molecules together in a chemical reaction to form polymer chains or three-dimensional networks). The collar is worn fairly tightly,to ensure friction. Bayer describes that the embedded active ingredients migrate from the collar matrix to form a microlayer on the collar surface, and then to direct contact point: remaining on the outer surface (lipid layer) of the dog’s skin and hair coat, (where neutral oils help them to diffuse and spread) enabling them to come into contact with the target parasites and display their efficacy. This offers the opportunity for a controlled, low dose-adjusted release (as the product wears off) that avoids peak (or low) intensities (as with "spot-on" products), depending on the concentrations of active ingredients within the lipid (fat) layeron the dog’s skin.
Because the slow release helps to avoid an elevated acute active ingredient exposure, it offers a formulation that appears appropriate for mixed dog and cat households: in which safety concerns arise about cats potentially ingesting critical amounts of insecticides through mutual grooming. It is not possible to apply any of the current pyrethroids (e.g. permethrin, deltamethrin) to the drug-sensitive cat species: their enzymatic systems are insufficient and low glucuronidation (addition of glucuronic acid to a substrate) decreases the capacity of the feline liver for xenobiotic metabolism (metabolism of drugs), leading to accumulation of toxic metabolites. In this case, the NOAEL standard for flumethrin is the same, and both the dog and cat collars are identical.
According to Bayer-sponsored research (based on in vitro studies of cell culture or tissue culture), imidacloprid and flumethrin work synergistically (their combined effects are greater than those achievable separately), such that together, they are 100 times more effective against fleas than imidacloprid alone. Depending on the activity level of the dog (and his propensity to get wet), the collar can provide optimal efficacy for 5-8 months. Critics dismiss Bayer’s description as marketing “techno-talk,” and despite its EPA classification of “low toxicity” if applied dermally, prolonged low-dose exposure to imidacloprid may affect liver and thyroid functions, and low to mid-dose oral exposures have been associated with reproductive toxicity in laboratory animals.
Eli: dapper dude
Transforming the public's perception of a
Pesticide into a Drug ...
In May of 2014, the FDA approved Bravecto® for marketing in the US. Merck Animal Health (Summit, NJ: MSD Animal Health worldwide) had launched the flavored chewable flea and tick treatment in parts of Europe a month previously. Merck claims the oral product will provide single-dose protection for up to 3 months (species dependent), providing an advantage over other chewables (typically 30 days; example: Spinosad, the active ingredient in Trifexis® and Comfortis® ), or use of “knock down” insecticides that consumers may not apply consistently. The product is dispensed in weight-specific doses through veterinary prescription.
The active substance of Bravecto® is (13.7%) fluralaner, a synthetic ectoparasiticide (antiparasitic drugs used to kill the parasites that live on the body surface) which is, like many new generation insecticides, a neonicotinoid:neuro-active applications chemically similar to nicotine. These chemicals act as a neurotoxin and interfere with the transmission of nerve impulses in insects. Fluralaner is among the new classification of carbamoyl benzamide phenyl isoxazoline (CBPI: or simply isoxazoline) insecticides that kill by binding to specific ligand-gated chloride channels (GABA-receptor and glutamate-receptors), causing paralysis and death.
Fluralaner is a systemically active treatment that binds to proteins in plasma and thus circulates in the bloodstream: like fipronil and other (example: spot-on) neonicotinoids, fleas and ticks must attach to the dog and commence feeding in order to be exposed to the “active ingredient.” The onset of effect is within 8 hours of attachment for fleas (C. felis) and 12 hours of attachment for ticks (Ixodes ricinus, Dermacentor reticulatus, D. variabilis and [US] ixodes scapularis). Consumers may mis-anticipate certain results: according to MSD Animal Health, because fleas and ticks must start feeding on the dog (ingest sufficient blood) in order to be killed by the insecticide, the risk of transmission of diseases with which they may be infected cannot be excluded (“unfavorable conditions”) ... whether killing is fast enough to prevent disease transmission cannot be determined. Merck asserts that Bravecto® can be used as part of a treatment strategy for the control of Flea Allergy Dermatits (FAD: an allergic reaction in dogs that are hypersensitive to “intermittent exposure to flea saliva” that is injected when a flea bites), since it “controls environmental flea populations” by killing fleas that may lay eggs (over time: “the flea life cycle is broken” ).
Harley: surfside sportsman...
The proportion of inactive ingredients in Bravecto® (see discussion above) is not disclosed on both US and non-US packaging, and listed as “secret” in Australian data sheets. This is “proprietary information” and only “hazardous” ingredients over 1% and/or “carcinogenic” ingredients in concentrations above .01% are listed in the chemical composition table. Merck’s US Material Data Safety Sheet captions only “CPBI, “starch,” [quotes added] polyethylene glycol, sucrose, and gylcerine,” with total product proportions that vary from 54.64% to 74.64%.
Detailed information on the toxicity and the fate of fluralaner in the dog's body (absorption, distribution, metabolism, excretion) and in the environment is sparse —(“The toxicological properties of the mixture(s) have not been fully characterized in humans or animals.”)—but users must contemplate that since it attaches to the protein in plasma and is slowly released and distributed to fatty tissues (where it kills insects), it would concentrate in kidney, liver, and muscle tissues: as the dog’s metabolic and renal systems recognize it as a toxin, and attempt to cleanse and repair the blood. Aslo notable was that no study was undertaken regarding the potential for “chronic/long term effects” (more than 168 days) of fluralaner (as Bravecto®) severally, or concerning the inactive ingredients as they might synergize and/or amplify it or each other; nor the issues of ordinarily unknown parameters for immune response of any particular dog that would lead to hepatic injury.
The Merck document discusses that the liver, as “the main elimination organ of CBPI” would likely be the main target of injury, but that a 90-day repeat-dose toxicity study (on rats) did not indicate damage, and as such, any degenerative changes “are considered to represent reversible metabolic effects and hence are of non-adverse character.” The liver is the singular organ in the body capable of regeneration.
Consumer advocacy groups monitoring the issue have been sharply critical that the trial done for Bravecto®, like Merial’s for Nexgard® (afoxolaner) was conducted/sponsored by Merck employees. And as they would have anticipated, less than two years later the FDA’s Center for Veterinary Medicine (CVM) had registered more than 5,300 complaints of adverse reactions to Bravecto®; more than half of which were submitted for a six month period through early January 2016; with a further 5,077 compiled by mid-October. By early May of 2017, the total had risen to 13,189. Similar to other neonicotinoids: sickness extended across violent gastrointestinal, neurological, endocrine, and renal turmoil to multi-organ toxicity/failure, blindness, euthanasia and death. Reports also include description of mydriasis (dilated pupils), nystagmus (uncontrollable eye movement), seizures, broad behavioral changes: particularly irritability and defensive aggression (possibly fear-induced owing to hallucinations) may accompany as the toxin accumulates in the adrenal and thryroid glands and the central nervous system. Observers caution that the CVM database is likely incomplete: see discussion below. Some reports describe reactions several months into treatment... coincidntally, according to Merck’s New Animal Drug Application (NADA 141-426), “Dogs achieved steady-state fluralaner concentrations by the third treatment period.” Other (uncompiled/non-reported) complaints include descriptions of consumers finding dead ticks attached to their dogs more than a year after discontinuing use, and questioning— with acknowledgment that there is no known antidote— how it can ever be flushed from the system.
Suri: assessing the competition...
AE reports also included leucocytois (elevated white blood cells) and complaints asserting that administration of Bravecto® had triggered development of Immune-Mediated Hemolytic Anemia (IMHA), a complex disorder in which the dog's immune system destroys its own red blood cells. In some cases, death had resulted.
A dog’s immune system comprises dedicated cells, proteins, tissues, and organs that represent his defense against infectious disease (fungal, parasitic, and viral infections) and foreign “toxins.” Antibodies (secreted proteins) in that system bind to foreign substances (antigens), to destroy them. These white blood cells (WBCs or: leukocytes) are produced and derived from multi-potent (gene activation potential) cells in the bone marrow (hematopoietic stem cells). Leukocytes are thus throughout the body, including the lymphatic system (circulatory and immune system: vessels that carry fluid toward the heart). The dog’s red blood cells (RBCs) serve the crucial function of carrying oxygen to the cells in the body and picking up carbon dioxide. A diseased condition (anemia) arises when the body’s immune system mistakenly begins identifying its own RBCs as antigens— because the surface of those RBCs is modified by a disease process, drug, or toxin— then, recognizing them as “foreign,” binds to them to initiate their destruction. The annihilation of RBCs (hemolysis) results in the release of hemoglobin, which can lead to jaundice, and then to anemia when the body cannot produce enough new RBCs to replace the ones being destroyed. The resulting disease is thus known as IMHA.
Merck is stern in its rebuke, that AE reports may be “anecdotes that are not substantiated by science and medical evidence.” How can that barrier of terminology be challenged? Consumer Safety Advocates monitoring AE reporting remain frustrated with a professional veterinary community that is generally averse to engage any discussion that might explore a possible causative relationship between administration of the drug and IMHA diagnosis, links to pancreatic or liver issues, or anything outside “common" or “… transient effects.” Even cases that are reported as “likely resulting from reaction to a ‘toxin,’” there is no agreement—or guidance— on would constitute “proof.”
In 2016, as the public relations aspect of the controversy became more troublesome, Merck Animal Health took the extraordinary step of posting a “Company Statement” on their website, with links to a surprisingly awkward (and edited) video featuring Merck’s Executive Director for its Technical Services division, adjoined to a “Bravecto®: Just the Facts” flyer for distribution to consumers… presumably from veterinarians. Observers deemed it a public relations misfire: as aspects of the flyer in particular would seem to merely draw attention to the escalating debate, with its bold type and jarring amonishment to disregard media and AE reporting, including: “A report does not mean causation”and “Global safety surveillance of Bravecto use has provided additional compelling evidence of the safety of the product.”
Oliver: "Who's more important? Your I-phone or ME ?"
BACK TO THE
In March of 2016, the European Medicines Agency (CVMP: Committee for Medicinal Products for Veterinary Use) granted marketing approval for MAH’s spot-on version of Bravecto®, in 5 weight-designated doses; with the US FDA following, in July. Five months earlier, based on a benefit vs. risk analysis, the CVMP had rejected Intervet International B.V.’s latest version (EMA/CVMP/750172/2015), which added a new target species (cats), because: “the data on user safety
CVMP determined that Intervet’s target animal study (TAS) “household simulation model”—which used a fipronil (the active ingredient in Frontline®) spot-on as a “surrogate” for fluralaner—was in-exact and irrelevant. Intervet had postured that this methodology demonstrated “no concern to the user” regarding quantifying the potential for indirect environmental exposure of fluralaner to the consumer. Intervet had offered its own TAS: in which dogs had been held in individual cages with carpeting as bedding, to simulate the home environment. According to CVMP: “This is a concern as plasma concentrations of fluralaner were measured in all control animals - which were housed separately - in the pivotal TAS study in dogs at up to 740 ng/ml which is considered high.” The CVMP noted that “a plasma level under 25 ng/ml is still proven to be efficacious for the indications of the product” and that as such “These results indicate that the [risk] exposure via the direct environment can be significant.”
“In the absence of fluralaner-specific information on exposure via the direct environment under normal conditions of use,” the CVMP estimated a dermal exposure level based on the main plasma levels in Intervet’s TAS, leading to a margin of exposure “insufficient to protect the user.” The CVMP also considered the issues of transmission to children via “hand-to-mouth contact” (petting/playing) with the dog, or “ingestion of house dust… a well-known scavenger for hydrophobic substances” (that repel water); and that the formulation, with an “elimination half-life of 21 days in the [dog]” was “hence not easily cleaned from the environment.” As the “cause of contamination of control animals in the TAS studies” was unclear and “not single study site specific or target animal specific,” the CVMP calculated a margin of error (MOE) of only 40 (not: 100), discussing that “the applicant did not perform specific studies to investigate the extent of environmental (household) contamination using fluralaner under field conditions.”
Hector: lazer focused...
Immediately appealing the decision, Intervet argued that “Generic/surrogate exposure modelling is an appropriate tool, and the chosen fipronil spot-on solution was an appropriate surrogate.” CVMP ultimately agreed with Intervet’s contention that “…risk of indirect exposure via cross-contamination is usually not addressed for [regulatory approval of] topically applied antiparasitic spot-on formulations,” and that “harmonizing” was therefore appropriate. CVMP accepted Intervet’s conclusion that “contamination of untreated control animals in the dog TAS study is considered most likely due to a single direct exposure to the active substance (cross-contamination) at or around the time of treatment [of the subject dogs].”
That is: Intervet employees conducting the TAS failed to control for cross-contamination.
Consumer safety advocates already frustrated by reports of adverse effects to the chew remain alarmed by Intervet’s desire to backward-engineer their novel product to an existing platform. More perplexing was the firm’s embrace of common interpretation that “the physicochemical properties of the active substance” are similar to ordinary US off-patent (non-prescription) antiparasitics: which had—at that precise moment—emerged as contentious with a rapidly growing US-based social media group
monitoring the phamacovigilance process.
Also of concern were excipients (solvents/humectants/stabilizers) that are, however, specific to Bravecto®/fluralaner, such as dimethylacetamide (DMA), a category 4 acute toxicity (H332; harmful if inhaled and H312; harmful in contact with skin) and category 1B reproductive toxicity (H360D at concentration >5%, may damage the unborn child). For that reason, a risk characterization for DMA would be provided in the user safety evaluation, owing to the possibility of dermal exposure to the consumer as the product is applied to the dog. A further risk characterisation (adverse systemic effects: acute oral exposure) for (14%; US: 13.2%) N,N-diethyl-m-toluamide (DEET) would be also be included: “A NOAEL of 75 mg/kg bw/day was reported. This NOAEL was derived from an oral capsule study in dogs terminated on day 5 due to severe (neuro)toxicity.” Used as a topical insect repellent, DEET is a known percutaneous (through the skin) penetration enhancer. In dogs, metabolism (oxidation) of DEET occurs in the liver, with toxicosis primarily involving the gastrointestinal tract and the central nervous system. A pivotal one-generation study in rats was submitted to address issues of reproductive toxicity, (in rats and) rabbits for developmental toxicity, and the assessment of the initial application for Bravecto® chewable by the CVMP was extrapolated regarding genotoxic potential and generalized safety characteritics.
Most surprisingly, Intervet/Merck’s labeling for the spot-on version of fluralaner differs, warning: “Use with caution in dogs with a history of seizures. Seizures have been reported in dogs receiving fluralaner, even in dogs without a history of seizures.” Consumer safety advocates are sharply critical that absent is information as to why this caution has not been extended to the already in-use product.
Murphy: deploy landing gear!!
Ever heard the term:
In Novermber of 2015, the European Commission approved Simparica™ for use in dogs and horses as a killer of four common European ticks and two types of fleas. Zoetis Animal Health (Florahm Park, NJ) promotes the chewable insecticide as faster working (8 hours for ticks) than Merial Ltd.’s Nexgard®, citing a comparative study. The US FDA approved it for the American market in February of 2016, indicated for use against adult fleas, flea home infestations (killing before they can reproduce) and the Lone Star, Gulf Coast, American and “brown dog ticks.” The company maintains that the active ingredient sarolaner maintains its efficacy consistently for (US version) 35 days (“spot-ons” are defined as heavy/overdose on application, then trailing off in effectiveness: a perpetual overdose-to-under-protected cycle).
After afoxolaner (NexGard™ ) and fluralaner (Bravecto™), sarolaner is the third active ingredient belonging to the isoxazolines classification as a veterinary prescribed systemic antiparasitic, in six weight appropriate dosages. Whereas Merial’s and Merck AH’s products are licensed from other companies, sarolaner was discovered and developed by its patent holder, Zoetis.
In its “Summary of Product Characteristics,” Zoetis states (as a product benefit): “C-sarolaner-related residues were widely distributed [through blood plasma] to the tissues” (bracketed text added). In its safety information warning, Zoetis openly cautions that “Simparica may cause abnormal neurologic signs such as tremors, unsteadiness, and/or seizures.” The document also discusses a “separate exploratory pharmacokinetic study” in which adverse reactions included (subsequent to an abrupt 2.5-fold rise in “plasma concentrations” after the 3rd monthly dose): vomiting/diarrhea, lethargy, anorexia, and abnormal neurological signs including ataxia (loss of muscle coordination, particularly in the extremities), tremors, disorientation, hypersalivation, diminished conscious proprioception (the ability to sense non-vision realized stimuli regarding position, motion, and equilibrium), and absent menace response (one form of “blink reflex”: reflexive blinking and body posture that occur in response to the rapid approach of an object, which may indicate damage to the cortical nerve).
The description continues: “This rise resulted ing in a Cmax (peak serum concentration) more than 7-fold higher than the mean Cmax at the maximum recommended use dose. No cause for the sudden increase in sarolaner plasma concentrations was identified. The dog was not treated, and was ultimately euthanized.” There is essentially no knowledge on tolerance related to breed, age, or specific health circumstances. Officially reported adverse effects include bloody vomiting, ataxia, convulsions and seizures, and death.
Ziggy: "It's cold and NO... I'm not interested in 'a swim!'"
“Not everything is known about a drug
when it is first marketed.
Due to the limited size and controlled nature
of pre-marketing clinical trials,
only the most common adverse events
will be observed and included in product
labeling at the time of FDA approval.
An accurate safety profile emerges only after
a product is marketed and the number and
spectrum of animals receiving the drug increases.
Adverse event reports are often the first signal
that a problem exists. ”
—US FDA, Center for Veterinary Medicine,
Pharmacovigilance of Veterinary Drugs:
Adverse Drug Event Reporting System (2001)
Milo: spotting a (potential) playmate...
What is “Adverse Drug Event”
Pursuant to ensuring consumer safety, the FDA’s Center for Drug Evaluation and Research now collects information on adverse drug experiences that occur after a prescription medication (a drug) is approved or marketed. This postmarketing reporting (pharmacovigilance) is required by a 2007 revision to the FDA’s Food, Drug, and Cosmetic (FD&C) Act: (Chapter VII, SubChapter H, § 760). That Act established “adverse event reporting” requirements which apply to the manufacturers, packers, and distributors whose names appear on the labels of over-the-counter (OTC) or behind-the-counter (BTC)
drugs marketed in the US.
The FDA’s Division of Compliance Risk Management and Surveillance (DCRM&S) enforces the Postmarketing Adverse Drug Experience (PADE) Reporting Requirements in an effort to ensure that the FDA is receiving data on rare, latent, or long-term drug effects that may not have been identified in premarket testing. The DCRM&S is responsible to confirm that PADE reports are accurate, complete, and submitted in a timely manner. Based on these reports, the division uses a risk-based approach to identify businesses and distributors for inspection and surveillance sampling to secure information related to public health. The inspections are evaluated to determine if regulatory action is necessary under the revised FD&C Act (Title 21 of the Code of Federal Regulations [CFR]).
The ADE reporting system depends on detection and voluntary self-reporting of adverse clinical events by veterinarians and dog/cat guardians. Consumer advocates stress that the ADE is the solitary official channel to impact review of a drug remaining on the market. In the case of veterinary drugs, the FDA’s Center for Veterinary Medicine (CVM) maintains a Cumulative Adverse Drug Event (ADE) Summaries database, intended to provide information on adverse effects that may not have been identified during pre-market testing of FDA approved animal drugs. As representative of the FDA's enforcement of the FD&C Act, the database, available online, has been criticized by food safety and consumer advocates as incomplete (and therefore inaccurate), and unreliable.
CVM cautions that the reports are, in many instances, only a collection of data, citing, (among other issues) that: the quality of reporting affects information; no information exists to determine the number of animals the drugs were prescribed and administered to (and that thereby, use of the reports to compare drugs is inappropriate); and most particularly, that widespread underreporting is likely.
Shadow: "I had no idea THAT was up there!"
In mid-March 2014, the U.S. Environmental Protection Agency (EPA) and two pet product companies announced an agreement to cease use of propoxur in flea collars. Propoxur is a carbamate insecticide that kills by reversibly inactivating the enzyme acetylcholinesterase (AChE: essential to successful nerve function arachnids). In 2009, the Natural Resources Defense Council (NRDC) filed a petition against the EPA for allowing the use of this toxic chemical despite that propoxur is a known neurotoxin and carcinogen (particularly, posing risk to brain and nervous system development in children).
Under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), a pesticide cannot be sold that may cause adverse impacts to human health or the environment. Based on this standard, in 2007 NRDC petitioned the EPA to cancel (discontinue approval of manufacturer registrations) the use of propoxur in pet products. Flea& tick collars work by depositing insecticide on the animal’s fur. In 2009, NRDC released a research report describing that high pesticide residue can remain on a dog’s or cat's fur for weeks after the collar is removed from the animal. Pursuant to that report, NRDC also petitioned for cancellation of tetrachlorvinphos (TCVP: another common carbamate pesticide in the collars). The EPA issued an initial finding in 2010 that propoxur collars presented unacceptable exposure metrics, and completed a risk assessment in September 2013: indicating health issues “of concern” to children from exposure to the collars.
In February 2014, NRDC filed a federal lawsuit to force the EPA respond to their 2007 and 2009 petitions, citing earlier severe restrictions on household use of other known neurotoxic pesticides. Under the March 2014 cancellation agreement, between the EPA, Sergeant’s Pet Care Products and Wellmark International (the two companies make products like Bansect®, Sentry®, Zodiac® and Biospot®), the companies will be allowed to continue producing collars containing propoxur until April 1, 2015. Distribution will be permitted to continue until April 1, 2016. Despite acknowledged health threats and FIFRA stipulations, according to a statement issued by the EPA, “agreement with the registrants as outlined here would be the best way to remove these products from the marketplace in an expeditious manner.” NRDC is critical of this lengthy phase-out period, regarding it a “slow retreat,” noting also, that flea collars can sit on store shelves for years before they expire. As such, the products may remain in the marketplace for sale to consumers well after the 2016 date: a situation similar to that with Hartz’s Blockade® product in 1987. Further, the agreement did not address use of tetracholoinphos in these products.
Piperonyl Butoxide (PBO) is a common factor of insecticide formulations with pyrethrins and a number of pyrethroids, including permethrin and tetramethrin products. Although it has no pesticidal action by itself, PBO is used as an insecticide synergist: since it enhances the potency of certain pesticides such as carbamates, pyrethrins, pyrethroids, and rotenone. Combining PBO with insecticides can increase the effectiveness of another chemical by impeding breakdown, thereby increasing the time it holds its toxic properties.
PBO inhibits the insect’s natural defense mechanisms, most importantly, the Mixed Function Oxidase system (MFO: the cytochrome P-450 system, responsible for intracellular energy transfer). The MFO system is the primary route of detoxification in insects, enabling the oxidative breakdown of insecticides and synthetic pyrethroids. Evaluation of sub-chronic and chronic studies examining the toxicity of PBO have led the EPA to classify PBO as a possible “Group C” carcinogen, and studies have identified an association between prenatal exposure to PBOs to delays in neurodevelopment in children.
Tucker: ardent adventurer...
ENDNOTES (for Part 1):  Journal of Pesticide Reform v.17, n.3 Fall97; Northwest Coalition For Alternatives To Pesticides. See also: Reregistration Eligibility Decision (RED) for Permethrin, EPA 738-R-06-017, April 2006.
 Organophosphates are biochemicals, esters of phosphoric acid. Organophosphates are the basis of many insecticides, herbicides, and nerve gases, effective by irreversibly inactivating acetylcholinesterase, an enzyme which is essential to nerve function in insects, humans, and many animals. They can be absorbed through the lungs or skin, or by eating contaminated food. Studies indicate a possible link to adverse effects in the neurobehavioral development of fetuses and children, even at very low levels of exposure: research spanning decades idenfities them as mutagents (genetic damage), as well as hormone and immune system disruptors. Organophosphates are widely used as solvents, plasticizers,
and Ethylene Propylene additives.
 Carbamates are organic compounds derived from carbamic acid: These insecticides kill insects by reversibly inactivating the enzyme acetylcholinesteraste; (see footnote 2, immediately above).
 FIFRA defines the term “unreasonable adverse effects on the environment” to mean: “(1) any unreasonable risk to man or the environment, taking into account the economic, social, and environmental costs and benefits of the use of any pesticide, or (2) a human dietary risk from resideues that result from a use of a pesticide in or on any food inconsistent with the standard under section 408 of the Federal Food, Drug and Cosmetic Act”; (click here).
Tank: a conspicuously dignified fellow
 Example: naphthalene, an “inert” in an imidacloprid product, showed clear evidence of cancer activity through inhalation (nasal cancers), as well as anemia, liver damage, cataracts, and skin allergies. An “inert” (unidentified) ingredient in the flea product Advantage® was implicated in the death of kittens who received doses within laboratory tolerances. (Kathleen Dudley, 2002: Are “Spot-On” Flea Killers Safe?).
 Status Report for PPDC, EPA. 1987. Inert ingredients in pesticide products (click here); Policy statement. Fed. Reg. 52(77):13305, Apr. 22 (click here).
 Examples: head-nodding; facial twitching; exaggerated blinking; gag responses; weight increase of the spleen, thymus, and adrenal glands; and/or atrophy of the thymus.
 Wallinga & Greer, 2000: Poisons on Pets, Heath Hazards from Flea & Tick Products; NRDC (click here).
Trevor: testing lateral G-force...
 According to an analysis by the Center for Public Integrity, more than 1,600 pet deaths related to spot on treatments with pyrethroids were reported to the EPA over a recent 5-year period, about double the number of reported fatalities tied to similar treatments without pyrethroids, such as Frontline® and Advantage®. Pyrethroid spot-ons also account for more than half of “major category” (brain damage, heart attacks, violent seizures) pesticide pet reactions reported to EPA in that period. The EPA received more than 25,000 reports of pet pesticide reactions (fatal, major, moderate, and minor) to OTC pyrethroid spot-on products; compared to 10,500 reports of all pet incidents related to shampoos, powders, sprays, collars, dips, mousses, lotions, and towels. This analysis does not consider how much of each product was used over the last five years, as the EPA
does not collect that information.
[10| The patent on fipronil has expired, and "generic" products include Sergeants® Sentry Fiproguard/Fiproguard Plus™ and Fidopharm PetArmour™.
 Journal of Pesticide Reform, vol.25, n.1 Spring 2005; Northwest Coalition For Alternatives To Pesticides.
 S-methoprene mimicks natural juvenile hormones of insects, and halts the growth of chitin, the substance that creates the exoskeleton in insects: therefore, treated larvae will be unable to mature into adults. Referred to as an Insect Growth Regulator (IGR), it is used to prevent an extended infestation (however, not against adult insects with already developed exoskeletons). Categorized as a biochemical insecticide (as mammals do not produce chitin, it is not directly toxic), it is used as a food additive in cattle feed, and to control mosquito infestations in drinking water cisterns. It has been suggested that methoprene is responsible for killing and stunting the growth of lobsters in Narrangansett Bay, RI.
 Information about reporting adverse events: click here. According to the report, in 2010: 27,216 reported incidents; 2009: 36,472 reported incidents. Though that may appear an improvement , most of the reduction was due to the number of incidents reported for one product: Sergeant’s Gold® Flea & Tick Squeeze-On for Dogs (EPA Reg. No. 002517-00080), which is also sold under the name Sentry Pro XFC® and TriForce Canine Squeeze-On®, which were discontinued (not recalled; and still being sold) in 2010, (and no longer appear on Sergeant’s website).
 Journal of Pediatrics, Vol 127 No. 3; 01 March 2011.
Among actions that EPA will pursue are: •1) Requiring manufacturers of spot-on pesticide products to improve labeling, making instructions clearer to prevent product misuse; •2) Requiring more precise label instructions to ensure proper dosage per pet weight; •3) Requiring clear markings to differentiate between dog and cat products, and disallowing similar brand names for dog and cat products; •4) Requiring additional changes for specific products, as needed, based on product-specific evaluations; •5) Granting only conditional, time-limited registrations to allow for post-marketing product surveillance.; •6) Evaluating certain inert ingredients; and •7) To improve regulatory oversight, require more standardized post-market surveillance reporting on adverse effects, require submission of more sales information so EPA can evaluate incident rates, and bring up-to-date the scientific data requirements on pre- and post-market testing so they align with FDA requirements.
 Isoxazolines with insecticidal and tickicidal efficacy are non-competitive GABA (gamma-aminobutyric acid) receptor antagonists: they bind to chloride channels in nerve and muscle cells, which blocks the transmission of neuronal signals. Affected parasites are paralyzed and die.
Bandit & Kelso: hot (though friendly!) pursuit...
 US Adopted Name “fluralaner” is: 4-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-m- ethyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide (CAS RN [864731-61-3]).
 The liver produces and secretes bile into the intestine where the bile assists with the absorption and digestion of dietary fat. The liver aids purification of the blood, by altering potentially harmful chemicals into harmless ones, and then: either secretes them with the bile for elimination in the stool, or back into the blood, where they then are removed by the kidneys and eliminated in the urine. The typical non-specific symptoms of degenerative liver disease (loss of appetite, nausea/vomiting, lethargy, etc.) are common first “symptoms” of “adverse reaction” to Bravecto®.
 (Also see: #18, above) The dog’s pancreas (endocrine and digestive system) produces insulin hormones (regulates the flow of glucose/sugar) and enzymes that break down fat and proteins to aid in the digestion of foods. When overburdened, the pancreas becomes inflamed, and the flow of enzymes into the digestive tract is disrupted; the enzymes may be forced out of the pancreas and into the abdominal area. These digestive enzymes will begin to break down fat and proteins in other organs… (the body begins to digest itself). Because of thier proximity, the kidneys and liver are prime targets of this progression.
 The notable exceptions are Advantage Multi® (imidacloprid + moxidectin) and Revolution® (selectamin); their ability to kill the L3 and L4 [larval] stages of heartworm and intestinal worms is due to a systemic action, so they are regulated
by the FDA.
that leads to hepatic toxicity
(Click to enlarge)
To report an adverse event associated with a pesticide (such as a flea and tick product), notify the National Pesticide Information Center (NPIC: 1-800-858-7378, 7:30am - 3:30pm PST) NPIC provides these reports to the EPA under a cooperative agreement.
Or: Click Here. Also, consider reporting the incident to the product's manufacturer: pursuant to FIFRA, manufacturers are required by law to submit reports of adverse effects to the EPA (click here).
To report a problem with a veterinary-prescribed drug: Click Here.
NEXT:Page 2- (Continued)
Flea & Tick Treatments:
Assessing Choices and Risks • Do Alternative Remedies Work?
What is Integrated Pest Managment?
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CLICK TO CONTINUE
NRDC Directory of Flea and Tick Products: Click Here
Farley: just a moment before landing a (wet!) kiss...
N.B.: This essay is written for informational (not educational) purposes. Our goal is to build awareness of concepts and define common terminology to stimulate creative thinking, so that you may effectively conduct your own research. We draw your attention to theories, issues or authors that are or may be important to the subject at hand, but do not consider that our interpretation is necessarily complete. This essay is, by nature, narrowly focused: there are numerous scholarly writings, as well as detailed EPA and/or FDA web pages, on this topic; which we encourage you to seek out. Use the links above. We would welcome your comments or suggestions! We are not medically trained, nor legal experts. We believe that the most important thing a dog guardian may do in his companion's lifetime, is work to build an understanding of manufacturing and regulatory processes for dog food, the basics of dog food labeling; and issues involving use of pesticides on and around household pets. We encourage you to discuss this topic thoroughly with your veterinarian.This essay is focused on products meant for dogs: it is important to remember that PEST CONTROL OR MEDICINE PRODUCTS INTENDED FOR DOGS SHOULD NEVER BE USED ON CATS. Web links are in blue & will illuminate when you pass your mouse over them: click to be directed to a site.
“The dog observes us, thinks about us, knows us. Do they then have some special knowledge about us, born of their attention us and to our own attention? They do.
In a non-verbal way, dogs know who we are, they know what we do, and they know some things about us unknown to ourselves. We're knowable by look and even more so by our smells. Over and above that, how we act defines who we are. For dogs, the identity of a person not just how s/he smells and looks; it is how s/he moves. We are recognizable by our behavior.
Even our most ordinary behavior, walking across a room in our characteristic style— is chock full of information that the dog can mine. All dog owners watch thier pups' growing sensitivity to the rituals that precede going for what in many dog peopled households is called a W-A-L-K.
And spelling that word instead of saying it is, of course, usually futile. Dogs can also learn the connection between the cadence of a spelled word and a subsequent walk, even if the latter does not immediately follow the former.
On the other hand, used in an unlikely context—say,
sitting in the bath—the spelled word will not evoke much interest.
Chances are slim you’re about to up and take a walk when naked and sudsy.
Dogs quickly learn to recognize shoe-donning, of course; we come to expect that grabbing a leash or a jacket will clue them in; a regular walk time explains their prescience; but what if all you did was look up from your work or rise from your seat before you dog was on to you?
If done suddenly, or if you cross the room with a purposeful stride, an attentive dog has all the information he needs. Habitual watcher of your behavior, he sees your intent even when you think you are giving nothing away. Dogs are very sensitive to gaze and thus to changes in our gaze. The difference between a head lifted up or angled down, away from them or toward them, is large for an animal so sensitive to eye contact. Even small movements of the hands or adjustments of the body attract notice. Spend three hours looking at a computer screen, hands tethered to the keyboard... then look up and stretch your arms overhead—this is a metamorphosis! The redirection of your intent is clear—and a hopeful dog can easily interpret it as a prelude to a walk. An acute human observer would notice this too, but we rarely let others oversee us so closely in our daily affairs.” —Alexandra Horowitz; Inside of a Dog (Click here to continue to page 2: Controversies & Remedies for Flea & Tick Problems)
You can brighten the long, lonely day of a needy dog:consider volunteering at a shelter. Your used but servicable linens, towels, bathmats, or cushions can provide comfort while he waits. Need help affording veterinary care? click HERE • Find low-cost spay neuter services: click HERE
Food & Safety Recalls/FDA Advisories for Dog Foods: click HERE
To think about: American taxpayers spend more than $1 billion annually to fund municipal animal shelters.
In those facilities, 14,000 animals are killed each day, often brutally: even in archaic gas chambers...
many within merely hours of their arrival: why are they called shelters?