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Part Two:
Common Choices and 

Risks

 
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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
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Traveling protection:
"Spot ons"

Chemical warfare: adapted for your dog...

As a profitable sales strategy, manufacturers drive the concept of insect killer/repellents that “travel” with the dog as a convenience response to the lifestyle of the modern consumer.  These “spot-applied” synthetic insecticides (paraticides) bear names—carefully developed through market research—that suggest not only protection but also safety (Guardian®, Advantage®, Frontline®, Advantix®, Interceptor®, and others).  To prevent him from licking it off: the oil-based drops are placed between the dog’s shoulder-blades. 

Few consumers have a reasonable understanding of how these products work: that as “systemic” pesticides, the poison ingredients bind to plasma and thereby circulate through their dog's bloodstream, pass through his internal filtering organs (liver and kidneys: which struggle to detoxify it), move through his intestinal tract (where 80% of his immune system resides), and are eventually eliminated in his feces and urine into the environment.

 

Imidacloprid

Common (now off-patent) active ingredients now include fipronil and the similar imidacloprid (Bayer’s Advantage® products and Seresto® collar), a nicotine-based (chloro-nicotinyl) insecticide (1994), belonging to a class of chemicals called neonicotinoids.  These chemicals act as a neurotoxin (toxic to nervesand cytoxin (toxic to cells) and terminate the transmission of nerve impulses in insects by binding to certain nicotinic acetylcholine receptors: causing hyperexcitation paralysis and death.  This is known as “energetic metabolism failure.” 

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 large-scale agricultural applications.  However, “less toxic” does not mean not toxic.  Premarket clearance studies (conducted by the manufacturer) do not evaluate for long-term toxicity, particularly chronic neurological and carcinogenic effects because regulatory approval does not require that.  

Imidacloprid is acutely toxic to some bird species, including sparrows, and its “half-life” persistence in soils can range from 107 days to over a year.  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.

Premarket clearance testing linked imidacloprid to increased cholesterol levels, thryroid lesions, liver toxicity, and with potential for damaging the liver, heart, lungs, spleen, adrenals, brain, and gonads; as well as association for incoordination, muscle weakness, labored breathing and demonstrated increase in birth defects.  

 

Fipronil

 

Fipronil (Class: Phenylpyrazole) was developed between 1985 and 1987 by Rhone Paulenc AG as a broad-spectrum phenylpyrazole insecticide, market-introduced in 1993.  This type of insecticide blocks GABAA-gated chloride channels in the central nervous system: disrupting the GABAA receptors and glutamate-gated chloride (GluCl) channels prevents the uptake of chloride ions (that allow muscles to relax) resulting in excess neuronal stimulation (hyperexcitation paralysis) and death of the target insect.  This is how nerve gas works (see below).

Fipronil disrupts progesterone and estradiol levels and offspring of exposed laboratory animals were smaller and grew slower than unexposed animals.  Premarket clearance studies indicated neurotoxicity to kidney function, and altered thyroid levels displayed through aggressive behavior, at all dose levels tested.

Formulas of these arylheterocycles also display high herbicidal activity.  The National Pesticide Information Center (NPIC) describes that fipronil 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.”

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. 

The US Environmental Protection Agency (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.  Fipronil is classed by the World Health Organization as a Class II “moderately hazardous pesticide.”  Still, fipronil (Frontline®, Hartz First Defense™,  Pet Armour®, Behaphar Fiprotec®, Sentry Fiproguard®) is supposedly among the “more safe group of spot-ons.”

The most reported adverse effects are related to impact to the central nervous sytem: ataxia (loss of muscle coordination); hyperreactivity (exaggerated reaction to stimuli), tremors, cramps, convulsions, abnormal gait, seizures, head-nodding, aggression, and weakness.

Modern-day
politics

In 2017, a political crisis erupted as authorities from Belgium's Federal Agency for the Safety of the Food Chain (AFSCA), after a two-month delay, succumbed to international pressure from German and Netherlands officials and admitted that test results of Belgian eggs revealed toxic-to-humans levels of fipronil.  The poison had been introduced into a detergent for killing chicken mites.  Across the European Union, hundreds of farms were closed: halting the sale of of tens of millions of eggs due for exporting; however, contaminated eggs may already had been sold for nearly half a year. 

 Destiny: "We're leaving... WHEN??"

Destiny: "We're leaving... WHEN??"

 

“REMEDIES”
that 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.  Pyrethroid spot-ons accounted for more than half of “major category” (brain damage, heart attacks, violent seizures) pesticide pet reactions reported to EPA in that period. Spot-ons were more than double the reports of all incidents related to shampoos, powders, sprays, collars, dips, mousses, lotions, and towels. This analysis does not consider how much of each product was used, as the EPA does not collect that information.[9]  It’s not clear how many more consumers experienced issues, but did not file complaints with the federal agency.  Few consumers are even aware that a reporting process exists.

In April of 2009, the EPA announced they were increasing investigations of these pesticides, widely advertised as “safe when applied as directed.”  Never clarified was why the agency did not reveal what was known or provide warning, while pets were sickened or killed.  No recalls were issued, and the EPA concluded that incidents were primarily the result of improper application by consumers.  It was suggested that this increase may have been coincided with the time-frame that some of these products began to be offered in retail outlets and through online vendors; and as such, those sales would lack traditional veterinary advice.

EPA-registered spot-on products are available as “non-restricted use” products that are commercially available through many sellers.  The EPA does not establish who can sell these products, and there is no prescription vs. “over the counter” (OTC) classification of pesticides: the manufacturer determines how they want
to distribute their merchandise.  Products that have a “systemic” mode of action fall under purview of the FDA.

After revisiting the safety of these products the agency had previously approved, in March of 2010, EPA announced it would 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 unanticipated synergy or interaction of some ingredients; (view PDF).

Unfortunately, these actions didn't address the larger concerns about the roles that 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.  Moreover, the review was narrow: other organophosphate and carbamate chemicals used in flea and tick collars, powders, sprays, and other products were not to be covered by the new protocols.[10]

It's important to understand that “spot-ons” are defined as heavy/overdose on application; then trailing off in effectiveness: a perpetual overdose-to-under-protected cycle.  This helps to explain why many dogs have an acute adverse reaction (example: vomiting, lethargy) that declines to sub-acute (non-observable) over time.

 1940s canine gas mask

1940s canine gas mask

How do these insecticides
work?

Nerve agents are a class of phosphorus-containing organic chemicals (organophosphates) that disrupt the mechanisms by which nerves transfer messages to organs.  The disruption is caused by blocking acetylcholinesterase (AChE), an enzyme that catalyzes the breakdown of acetylcholine (Ach), a neurotransmitter.

When a normally functioning motor nerve is stimulated, it releases the neurotransmitter Ach, which transmits the impulse to a muscle or organ.  Once the impulse is sent, the AChE enzyme immediately breaks down (hydrolizes) the Ach in the synapse in order to allow the muscle or organ to relax.  By forming a covalent bond where Ach would break down, it thus builds up and continues to act so that any nerve impulses are continually transmitted and muscle contractions cannot stop
(neuromuscular paralysis).

 

The concentrations of pyrethroids (synthetic pesticides) in OTC spot-on products (example: Farnam Bio-Spot®, Hartz Ultraguard®) 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 through skin,” (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 and leading to brain damage and death.

The label of Hartz Ultraguard® Flea & Tick Dip for Dogs, (a liquid intended for literally soaking a dog 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, thereby dispersing the toxin across the food chain.


 

 Honey: A gull beckons overhead... "What freedom must be, to fly above!"

Honey: A gull beckons overhead... "What freedom must be, to fly above!"

 

Regulatory Review: a Failure of Government

 

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 briefly interrupted (not 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, posturing that injured or killed animals were likely aged, too small, sick or debilitated to begin with, or that the product was being used improperly; during which time (September of 1987) it added a precautionary wired-on neck tag (“revised supplemental labeling”) to the cans as an interim step.  The EPA mandated tag would address the lack of information on the cans themselves.

The use of any product on the market to control fleas on pets is associated with a degree of hazard to the animal...”
— Claude Kissen, Vice President, Hartz Mountain Corp., 1987

About the lack in labeling, an EPA entomologist observed: “It wouldn't have sold 5 million cans. Would you buy a product that would say that your animal may have seizures, tremors or vomit?” 

 

Hartz's test methodologies:
no application rate,
no margin of safety
no violation of law

Blockade® was registered by the EPA in 1985. Because the product's active ingredients were familiar to the agency and considered “safe,” the EPA sought only limited data on the toxicity of the new combination of N,N-diethyl-m-toluamide (DEET: registered as a mosquito repellent for human use), and Fenvalerate (an agricultural pesticide, registered for use on domestic animals, including pets).  But when the agency began fielding complaints, it asked Hartz to submit further data on the toxicity of the combination: “[by] mid-March -- before the next tick season.”  But in just six months, six million 6-dose cans of the product had already been sold.

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”; (view PDF). 

The active ingredient phenothrin (sumithrin and d-phenothrin) bioccumulates in mammals, because organophosphates inhibit the detoxifying activity (the cleavage of chemical bonds through hydrolosis) of esterases enzymes in blood.  It is also in EPA’s highest toxicity group for bee toxicity, and is extremely toxic to aquatic life, with concentrations as low as 0.03 ppb lethal to killing mysid shrimp.  Phenothrin has a “half-life” environmental persistence of up to 60 days depending upon the soil type, and has been found to possess antiandrogen properties in humans via environmental exposure.

Scientists theorized that the lax EPA standards failed to account for the percutaneous characterization of the insect repellent DEET, (its ability to permeate the skin after application) which may carry the Fernvalerate ingredient and achieve systemic absorption through the vascular system.

Eventually, Hartz paid the EPA $45,000 (half the original penalty, and accompanied by a denial of responsibility) to settle charges that they failed to report animal illnesses and deaths: after months of delay, EPA observed that “We did not consider it to be reporting when we had to send inspectors out to get it.”  The company removed Blockade® from the market in 1988 for further tests, then reintroduced a subtly reformulated replacement in 1989.  EPA registration was cancelled in 1999.

 
 

EPA cancels registration of phenothrin

In 2005, the EPA cancelled permission to use phenothrin (sumithrin and d-phenothrin) in certain flea and tick products, at the request of Hartz itself.  The products were linked to thousands of adverse reactions between 2000 and 2002, including hair loss, salivation, tremors, seizures, and anemia in dogs; and deaths of dogs and cats.  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 for years Hartz was clearly aware that the products were dangerous, and even once discontinued, they were not withdrawn from retail shelves and persisted being sold absent warning, often diverted to discount outlets.  Additonally concerning was that nearly 92% of the ingredients were “inert,” or company trade secrets.  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.

 
 Boscoe and Clifford: Who's just arrived?

Boscoe and Clifford: Who's just arrived?

 

“Next Generation” Products:
Market Competition and
Pesticide Resistance

 

The Lanham Act (1946)

Product introductions reflect market competition and today, are augmented by necessity, as patents on some of the dominant pesticides have expired.  The most notable example is Merial’s (Deluth, GA) fipronil (prescription-only Frontline®) which expired in 2011.  In anticipation, competitors had been preparing generic “over the counter” versions that could be offered at any retail outlet; but by then, Merial had a track record of aggressively litigating against competitors.  Plaintiffs in Horizon Valley Generics Inc. et. al. v. Merial Limited et. al., 1:13-cv-00147-UNA U.S. District Court, District of Delaware (Wilmington), argued that “Merial has litigated its fipronil-related patent rights to stop perceived competitors from bringing to market, or even attempting to develop, products that could potentially compete with its Frontline series of products.”

Merial had already moved a decade earlier (2000) to maintain its elevated “veterinarian only” status by introducing Frontline® Plus, combining fipronil with S-methoprene, an insect growth regulator (see: below).  In BASF Agro BV et al. v. Cipla Ltd. et al., case number 3:07-cv-00125, in the U.S. District Court for the Middle District of Georgia, and Merial Limited v. Cipla Limited, Appeal No. 2011-1471, in the U.S. Court of Appeals for the Federal Circuit, courts found that FidoPharm’s PetArmorPlus™, along with other Velcera products combining fipronil and S-methoprene, (and Cipla manufactured imports) infringed on the patent covering Merial’s combination, and that, although the fipronil patent had expired, the fipronil-methoprene combination was still protected.  The 2011 finding of contempt of a previous injunction (collectively: “Cipla”) included an order for the seizure of existing US inventory for presentation to Merial for destruction.

 

pesticide resistance:
a "heritable change"

 
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New products are also borne of market necessity, as insecticides inevitably lose efficacy over time.  Fleas and ticks have developed resistance and even immunity to the first generations of poisons in some geographic areas.  Pesticide resistance describes the decreased sensitivity (a “heritable change”) of a pest population that is reflected in declining control of a product that was previously effective.  Pest species evolve pesticide resistance via natural selection: the most resistant specimens survive and pass on their genetic traits to their offspring.

Selective Pressure

The theory of the action of selective pressure and how organisms partner was first fully developed by Charles Darwin, as the biological process that spurs evolution.  Darwin’s theory described the process whereby organisms that adapted to their environment and thereby tended to survive and produce more offspring was unintentional (natural); not one of artificial selection (example: animals bred for specific characteristics). 

Random mutations in the genetic material (genome) of an organism will vary, and offspring can inherit such mutations.  As their genomes interact with the environment, variations in traits arise.  Darwin described the process as “the principle by which each slight variation [of a trait], if useful, is preserved.”  The environment of a genome includes the molecular biology in the cell, other cells, other individuals, populations, species, as well as the physical (abiotic) environment.  In the instance of “nuisance” insects, that environment would be altered by human-applied pesticides.  Because individuals with certain variants of a specific trait (ability to resist a pesticide) tend to survive and reproduce more than individuals with other, less successful, variants, the population progressively evolves to withstand that pesticide.

combat_insects.jpg

The characteristics of an insect that actually interact with the environment are known as its phenotype.  Natural selection acts on the phenotype, but the genetic basis of any phenotype that gives that phenotype a reproductive advantage may become more common.  Over time, a population might specialize (microevolution) for adaptive need of ecological function; and eventually, a new species can emerge (macroevolution). 

Pesticides that do not break down quickly (lengthy “half life”) contribute to selection for resistant strains even after application ceases,  because consuming repeated small amounts supports developing immunity to the normal (or even multiplied) lethal dose.  Increasing frequency of application in response merely exacerbates the problem.  Additionally, a pesticide may eradicate a competitive species, allowing the target insect population to expand; in turn, requiring more pesticide. 

Developed resistance may involve rapid excretion of toxins, or secretion within the body that separates them from tissues, and decreased permeability of sensitive cell walls.  Alternatively, the number and/or sensitivity of biochemical receptors that bind to the pesticide may be reduced; or, increasing  the number of copies of genes that produce protective enzymes (example: glutathione S-transferase) that metabolize the pesticide into less toxic chemicals.  In some cases, insects have evolved changed behaviors (behavioral resistance) that increase survival rates.  Chemical manufacturers prefer not to acknowledge the concept of pesticide resistance, calling it “field resistance” related only to the failure of choice of product.

 Neo: a momentary repose... 

Neo: a momentary repose... 

 

Recent Introductions
and the meaning of  “Market Value”

Biotransformation
into Metabolites

As a classification, many spot-ons are associated with aggression and severe depression (serotonin is produced in the digestive tract), lethargy, destruction of kidney tissues, and symptoms concomitant with aggravated liver toxicity (the liver is the body's primary detoxifying organ).  Moreover, metabolites (the breakdown of the chemical into new chemical compounds during the metabolism process in the body: biotransformation) may in fact be more toxic than the active ingredient the consumer identifies in in order to choose a product purchase.

Even in multiple-combination pesticides, more than 80% of the ingredients are are captioned as “inert” and as such, neither the consumer or the veterinarian has means to gain knowledge about what they are, or what their toxicological effects might be.


 
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What are insect growth regulators?

An Insect Growth Regulator (IGR) is a synthetic biochemical mimic (juvenoid) for natural juvenile hormones of an insect.  These hormones control how long it remains in each larval or nymphal growth stage, and when it turns into a reproductive adult.  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.  Juvenoids break the biological life cycle of the insect to prevent extended infestations.  Examples include: S-methoprene and pyriproxyfen (fleas).

Other IGRs are chitin synthesis inhibitors, which block development of chitin (polysaccharide-type carbohydrates: primarily starch, cellulose, or glycogen molecules bonded together that form the insect’s “skin”) so that the insect can’t form a new exoskeleton or shed the old one: affected insects die during the molting process.  Adults with already developed exoskeltons are not affected by IGRs.  As mammals do not produce chitin, these IGRs are selectively toxic to insects and are used as food additive in cattle feed, against stored product pests that are used in pet foods, and to control mosquito infestations in drinking water cisterns.  IGRs are also packaged as total release aerosols (foggers), crack and crevice aerosols and emulsifiable concentrates.  Despite this assumption, it has been theorized that methoprene is responsible for killing and stunting the growth of lobsters in Narrangansett Bay, RI.  


The active ingredients in next-generation Frontline Plus®  (Now also: PetArmour® Plus, Part of Fidopharm's range of generics) are fipronil (9.8%) and S-methoprene (8.8%). 

In laboratory tests, fipronil was shown to cause kidney damage, altered levels of sex and thyroid hormones, and thyroid lesions; S-methoprene has demonstrated liver enlargement and kidney destruction.

Merial Limited (Duluth, GA) introduced Frontline® Tritak™ for dogs in 2012, responding in part to the waning efficacy of 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 (5.2%) cyphenothrin (class: synthetic pyrethroid) to the 2000 Frontline Plus®  formula, Merial claims the stronger (“comprehensive… triple action”), 30-day formulation is waterproof and will begin killing adult fleas in 5 minutes; then 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 combined solely 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.

 

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 (class: carbamate) and permethrin (class: synthetic pyrethroid).  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 (class: IGR/developement inhibtor; Novartis: Program® and Virbac: Sentinel®) and S-methoprene (Certifect®).  Merial’s veterinarian-dispensed Certifect® was developed as their patent on Frontline® products was expiring, adding amitraz (class: amidine) to fipronil and S-methoprene.

Amitraz (1969: Boots Co., UK) is a widely used pesticide (agricultural: livestock and fruit) and scabicide (scabide mites); with repellent effect for ticks.  It has seen a resurgence in the last decade for canine use because of its synergistic capabilities when paired with spot-ons with imidacloprid or spinetoram that are effective against fleas, but not ticks.  It is now used in collars, dips, sprays, spot-ons, shampoos and powders.  The mode of action is different from synthectic pyrethroids or organophosphates: due to its antagonistic effect on octopamine receptors of the central nervous system (brain), causing parasites to become hyperexcited and paralyzed.  Symptoms of poisoning can include low blood pressure and pulse, hypothermia, lethargy, inappetence, vomiting, increased blood sugar and digestive problems; however, its non-systemic nature indicates that these effects are reversible or at least recoverable.

 

 Sodium ion nerve channel

Sodium ion nerve channel

Merk Animal Health introduced prescription Activyl® and Activyl® Tick Plus spot-on flea and tick control in 2012.  The active ingredient is DuPont's indoxacarb (2000: Steward™ , Avaunt™ and Technical Indoxacarb™), an oxadiazine pesticide which blocks sodium ion nerve channels.  Indoxacarb was developed to combat growing resistance of larvae of winged insects to pyrethroids in agricultural applications.  In these products indoxacarb is paired with permethrin (1973).  Inert (undisclosed) ingredients comprise nearly 45% of the product.   

Sodium Ion Nerve Channels

Sodium channels are integral membrane proteins that form ion channels, conducting sodium (NA+) ions in excitable cells (example: neurons), that move through phases of "action potential" (resting/active/inactive). 

The rapid and selective transport of Na+ through sodium selective ion channels is essential for initiating electrical signalling in living organisms.  Blocking these gates (spontaneous depolarization) leads to repetitive discharge: a chemical hyperexcitation-paralysis and death.

 

Adverse canine reactions to indoxacarb include weakness, depression, salivation (drooling), abnormal gait or movements, inability to stand, and head tilting suggestive of neurological impairment.  There is no antidote for indoxacarb poisoning, with treatment consisting of discontinuing exposure and supportive measures for specific symptoms.  Permethrin is listed as a “restricted use” substance by the US Environmental Protection Agency (EPA)[23] due to its high toxicity to aquatic organisms. 

Although Zoetis Inc. (Pfizer) does describe that its prescription spot-on Revolution®/  Sronghold® (Selamectin, [1999]; class: macrocyclic lactone; for heartworm, fleas, ticks, mites) “enters the bloodstream through the skin,” the term “systemic” is quietly sidestepped.  Selamectin treats infections of heartworms, fleas, ear mites, sarcoptic mange (scabies), and certain types of ticks.  Absorbed into the body through the skin and hair follicles, it travels through the bloodstream, intestines, and sebaceous glands; parasites ingest the pesticide drug when they feed on the dog’s blood.  By definition then, it is “systemic.”

It is structurally related to macrocyclic lactone-class Ivermectin and Milbemycin oxime, as it activates glutamate-gated chloride channels at muscle synapses, allowing chloride ions to overwhelmingly accumulate and causing neuro-muscular paralysis.  Symptoms develop usually 5 to 24 hours after treatment, manifesting initially as vomiting, and can last for several days until coma. Generally, poisoning is more serious and prognosis is worse if the symptoms develop faster.  There is no antidote for indoxacarb or ivermectin poisoning.  Treatment consists in in preventing further exposure together with supportive and symptomatic measures.

 
 Carrie: the day is fading... happiness not!

Carrie: the day is fading... happiness not!

 

The Blood-Brain Barrier

Invermectin is not safe for dogs with a mutation in the MDR1 gene that affects the blood-brain barrier (BBB) and makes it more permeable to such compounds than in the normal case.  These dogs are sensitive to compounds that may thus penetrate this highly selective semipermeable membrane barrier that separates circulating blood from the brain and extracellular fluid in the dog's central nervous system.  The membrane works through (1) tight junctions that restrict movement of substances between the endothelial cells (interior of blood and lymphatic vessels); (2) specific transport proteins that determine which substances can cross the barrier transcellularly; and (3) enzymes that may degrade or alter substances prior to passage.

Commonly affected breeds include the (% frequency): Collie (70%), Long-haired Whippet (65%), Australian Shepherd (50%, also mini), McNab (30%), Silken Windhound (30%), English Shepherd (15%), Shetland Sheepdog (15%), English Shepherd (15%), German Shepherd (10%), Herding Breed Cross(10%). Other less affected breeds are: Old English Sheepdog, Border Collie, Berger Blanc Suisse, Bobtail and Wäller; and mixed-breed dogs can also be affected. The only way to be sure that a dog is affected or not is to test for it. 

Even dogs without the MDR-1 genetic mutation may have a compromised blood brain barrier due to injury or diseases. Hypothyroidism has been found to compromise the BBB.  Zoetis seeks to distance its product from other spot-ons: “Revolution® is a medication...  not a pesticide registered by the Environmental Protection Agency (EPA).” 

 

Isoxazoline ectoparasiticides

 
 Isoxazoline

Isoxazoline

 

In mid-2016, the US FDA approved Merck’s Bravecto® prescription topical, a backward-engineered version of its controversial fluralaner chew.  One of the new classification Isoxazoline ectoparasiticide parasitic (see next page), fluralaner inhibits transmission of neuronal signals by binding γ-aminobutyric acid (GABA)-gated chloride channels (GABACls) and L-glutamate-gated chloride channels (GluCls); affected parasites are paralyzed and die.  It is comparable in potency to fipronel (class: phenylpyrazole ectoparasiticide).

The oral version is linked to a broad range of adverse behavioral/neurological reactions, vital organ toxicity, seizures, and death, with consumers generally unaware that that there is no antidote for fluralaner poisoning: treatment consists only in preventing further exposure together with supportive and symptomatic measures.  It has been the subject of intense and acrimonious debate: as consumer safety advocates drawing attention to the failures of the regulatory approval and reporting system have drawn fire from the company’s legal division.  See: discussion on next page.


 

It's on the Label:

The Normal Use as “Overdose”? 
… Death as a “Side Effect”?

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collars and tags

How do collars work?

 
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Cheaper, older-style collars work by emitting the toxin as a gas (once the collar is stretched to break its outer casing): thus consumers generally complain that they only kill or repel in close proximity to the collar itself.  Similarly ineffective are second-generation products that shed microparticled (powdered) chemicals that the dog may inhale or consume through self-grooming. 

Newer collars continuously release repellent chemicals and spread over the pet in the natural oils of the hair, coat and fat-layer of the skin. The “active” ingredients then adhere to the hair and skin where an insect bites and consumes the pesticide.  New-generation collars emit chemicals that kill on contact, before biting.

Pesticides in modern collars that last an entire season are typically neurotoxins that interrupt transfer of nerve impulses, leading to hyperexcitation paralysis and death. 


Among choices are Merck's 6-month Activyl® and Scalibor® Protector Band, both which use a 4% concentration of Deltamethrin (1978), a synthetic pyrethroid ester insecticide (generic products include Sentry®  Dual-Action). 

Deltamethrin has an environmental half-life (the measure of time it takes for half of the applied amount to break down into metabolites) ranging from 5- 209 days. 

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”); an so, unable to “de-excite,” the insect is paralyzed, and dies.  

Notable is that 96% of the ingredients in these collars 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 or synergistic 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.

Virbac Animal Health, asserts that its Preventic® Tick Collar for Dogs holds a higher efficacy rate, and also (as does Merial for its Frontline®), claims that it is “non-systemic.”  The active ingredient, a 9% concentration of Amitraz (formammidine pesticides: a triazapentadiene compound, performs as an adrenergic agonist), works in a similar manner to deltamethrin, and is used as a repellent, arachnicide, (insecticide for arachnids), and pesticide synergist.  91% of the contents are inert/protected trade secrets about which the consumer cannot
acquire information.

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 (according to industry conducted premarket clearance)following this type of use is “in-coordination” and sedation of the dog... which can last up to 72 hours.

Seek emergency veterinary medical treatment [for symptoms that include]... in-coordination, slow heart rate, decreased body temperature or death.”
— Vibac US (product warning for Preventic collar)

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.  Among its effects on dogs are depression of the central nervous system, bradycardia (abnormally slow heart rate) with attending respiratory distress, confusion, fatique, and unsteady gait; and  hyponatremia (low sodium plasma levels) with corresponding nauseau, fainting, seizures, and coma.

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”

 Henry: surfside sportsman... 

Henry: surfside sportsman... 

The Quest for Longer-lasting products

 

In 2013, Bayer introduced its Seresto® collar to the US.  The active ingredients are 10% imidacloprid (class: neonicotinoid; 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.

Bayer identifies their (patented process) 8-month collar as “a polymer matrix composition” (polymerization is a process of reacting small monomer molecules together in a chemical reaction to form polymer chains or three-dimensional networks).  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 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) layer on the dog’s skin.  For dogs that swim or are bathed often, efficacy is reduced to 5 months.

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 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.  Publicity materials do not address whether this correspondingly decreases the ordinarily expected margin of safety for either, or both as they may impart different metrics for metabolites.

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.

Dogs would generally tolerate flumethrin well, since toxicity is about 1000x higher to insects and other arthropods than to mammals.  Toxicity to the dog would be higher through dermal exposure (especially from irritated skin or open wound), and symptoms of poisoning would include ataxia (uncoordinated movements), hyperactivity, tremors, paresthesia (skin sensation of tingling, tickling, prickling), lethargy, hyper-salivation, vomiting, diarrhea, and
urinary incontinence.

 

Insecticidal tags

Peak Marketing, LLC. (Durvet: Blue Springs, MO) offers its 4-month Spectra SHIELD® Collar Attached Medallion (YT-1601: 2012) as an alternative to topicals.  The 4-month continuous release tag attaches to the dog’s collar, combining (10%) Zetacypermethrin (class: synthetic pyrethroid) and (20%) Piperonyl Butoxide (mixed function oxidase inhibitor) to kill adult fleas and blood-feeding stages of ticks by spreading over the hair coat.  The tag is sold in 4, 6, and 8-gram sizes (weight determined). 

Highly toxic to fish, cypermethrin is used as an insecticide in large-scale commercial agricultural applications, although resistance develops quickly with frequent exposure.  Disruption of sex hormones, and chromosomal abnormalities in bone marrow and spleen cells in laboratory animals have been noted.  Long-term exposure has been shown to induce dopaminergic neurodegeneration: the progressive loss of structure or function of neurons, including death of neurons (examples of neurodegenerative diseases are amyotrophic lateral sclerosis, Parkinson's, Alzheimer's, and Huntington's).   A 1993 dye-transfer assay demonstrated that cypermethrin inhibits “gap junctional intercellular communication” (GJIC), considered to play important roles in maintenance, growth and differentiation of cells, and in tissue homeostasis (stable equilibrium).  Piperonyl butoxide (PBO) is used as an insecticidal synergist to increase potency of carbamates, pyrethrin, and pyrethroids. 



Endnotes


[9]  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), also sold as Sentry Pro XFC® and TriForce Canine Squeeze-On®, which were discontinued (not recalled).

[10]  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.  Consumer safety advocates complain that little meaningful progress has been made to realize these goals.

The dog observes us, thinks about us, knows us. Do they then have some special knowledge about us, born of their attention to 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...
— Alexandra Horowitz: Inside of a Dog
 Bradley: naturally athletic...

Bradley: naturally athletic...


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