Toxicity Mechanisms and Selective Toxicity

Mechanisms of Toxicity

• Receptor-mediated mechanisms
• Enzyme-related mechanisms
• Direct physical damage (free radicals)
• Immune system-related mechanisms
• DNA-related mechanisms
• Reproduction/development-related mechanisms

Selective Toxicity

• Pesticides rely on selective toxicity, where the agent is significantly more toxic to the target species than to non-target species
• Achieved through differences in toxic effect, differences in toxicokinetics, and selective exposure

Toxicology

• Involves identification and classification of the poison
• Physical and chemical properties of the poison
• Biological effects and fate of the poison in the body
• Examines effects at a population level

Bioaccumulation and Biomagnification

• Bioaccumulation: gradual accumulation of a toxin over time within an animal
• Biomagnification: process by which a toxin increases its concentration in tissues of animals as it travels up the food chain

Primary and Secondary Poisoning

• Primary poisoning: direct exposure to the toxin
• Secondary poisoning: toxicity that occurs through contacting or ingesting another organism that has been directly exposed to the toxin

Sources of Toxins

• Metals
• Bacterial and fungal toxins
• Pharmaceuticals
• Household pesticides
• Poisonous plants and animals

Margin of Safety

• Calculated as the dose that is lethal in 1% of animals divided by the dose that is effective in 99% of animals (LD1/ED99)
• Expressed as the weight of drug or toxin per kg/g of animal weight

Toxicokinetics

• Describes the movement and fate of toxins once they contact or enter the body
• Four primary processes: absorption, distribution, metabolism, and excretion

Absorption

• Through ingestion (oral route)
  • Factors affecting absorption: pH, GI motility, GI surface area, lipid solubility
  • Barriers: digestive enzymes, alteration in pH, motility of the GI tract, interactions with food and other drugs in the GI lumen
• Through the skin (percutaneous route)
  • Toxins pass through the skin via passive diffusion and enter the systemic circulation
• Through the airways (inhalation)
  • Absorption occurs via the lungs
  • Epithelial cells lining the alveoli are thin, allowing for rapid diffusion into the blood

Distribution

• Rate of distribution depends on blood flow and rate of diffusion out of the capillary bed and into the tissues
• Toxins are distributed into different body fluid compartments
• Eventual distribution is determined by tissue affinity

Metabolism

• Alters the physical properties of the toxin from lipophilic to hydrophilic
• Occurs primarily in the liver
• Most often terminates the effects of the toxin, but can also initiate the effects of the toxin
• Phase 1 reactions (catabolic, often involving cytochrome P450 enzymes) → Phase 2 reactions (anabolic, leading to inactive products)

Thermoregulation

• Elevated body temperature (hyperthermia) is characterized by an increased thermoregulatory 'set point', often associated with infectious diseases.
• Response to hyperthermia is to decrease heat production and increase heat loss.
• Reduced body temperature (hypothermia) is characterized by a decreased thermoregulatory 'set point', which can occur prior to giving birth in some species or during hibernation.
• Response to hypothermia is to increase heat production and decrease heat loss.

Thermoneutral Zone

• The thermoneutral zone is the range of ambient temperatures at which temperature regulation is achieved without regulatory changes in heat production or evaporative cooling.
• Active compensatory mechanisms are employed above the upper critical temperature and below the lower critical temperature.
• Body size and shape are important factors, with smaller, thinner animals losing heat more readily and larger, fatter animals gaining heat more rapidly.

Heat Stress

• Heat stress clinical signs include increased water intake, decreased appetite, decreased fertility, decreased weight gain, decreased milk production, reduced exercise performance, illness (heat stroke), and death.
• Environmental factors affecting heat stress include ammonia concentrations, water temperature, pH, and stocking density.

Environmental Effects and Degradation

• Climate change can make suitable habitats for both domestic and wild animals unsuitable or shift geographically.
• Deforestation and loss of habitat, pollution, and human interaction (inappropriate diets, conflicts, and disease exchange) are environmental effects that can impact animal welfare.

Animal Welfare

• Animal welfare is the concern for an animal's wellbeing, associated with the concept that animals should be humanely treated and not unnecessarily suffer.
• The concept of animal welfare has evolved over time, with a growing circle of concern and advocacy for animal health.
• Timeline: 500 BCE - Ancient philosophers advocated not eating animals, 400 BCE - Religious edicts forbidding the consumption or mistreatment of certain animals, Early 20th century - Prevention of Cruelty legislation, Late 20th century - Concept of 'duty of care', and Now - Change driven by public behavior rather than legislation.

Genetics

• The Law of Segregation: Two alleles for each trait segregate in gamete formation and offspring inherit one genetic allele from each parent.
• The Law of Dominance: An organism with alternate forms of a gene will express the dominant form.
• The Law of Independent Assortment: Excluding linked genes, genes for different traits are sorted separately.
• Genetic principles and animal breeding technologies are crucial for improving animal health, production, and wellbeing.

Genetics Terminology

• Gene: The shortest nucleotide sequence that codes for a specific function or trait.
• Chromosome: A long strand of DNA and associated proteins present in the nucleus of every cell.
• Locus/loci: The specific location of a gene on a chromosome.
• Alleles: Alternate forms of a gene.
• Dominant: An allele that covers up the effect of the other allele.
• Recessive: The allele whose effect is covered up.
• Trait: Any observable or measurable characteristic of an individual.
• Phenotype: The measurement of a trait.
• Simply inherited trait: A trait only affected by a few genes.
• Polygenic trait: A trait affected by many genes with no single gene having an overriding influence.

Disease Investigation

• The first step in investigating a disease is to identify the origin of the disease: type of pathogen, genomic sequencing, and testing if the pathogen isolated from an animal will cause disease in the animal.
• The next step is to investigate sources of disease: antibody testing the animal, humans, and local wildlife, and sampling the environment.

Rabies and Australian Bat Lyssavirus

• Rabies is caused by an RNA virus called Rabies lyssavirus (Rhabdoviridae), with several genotypes that may be host or geographically associated.
• Rabies affects all warm-blooded animals but primarily mammals, and is transmitted when the virus comes into contact with fresh wounds or unprotected mucous membranes of non-vaccinated animals/people.
• Signs of illness may appear within 10 days and several months, and death typically occurs within 10 days after clinical signs are present.
• Control options: humans - pre-exposure vaccination or post-exposure vaccination and immunoglobulin administration, domestic animals - vaccination and desexing, wildlife - oral bait vaccines (sylvatic cycle).
• Australian bat lyssavirus works similarly to rabies in terms of its clinical signs and its 100% mortality rate after the presentation of these clinical signs.

Antimicrobial Stewardship

• Antibiotics are used to treat or prevent bacterial infections in humans and animals, but bacteria and other microorganisms naturally develop resistance to antibiotics over time through genetic changes.
• These resistance genes can also be passed between different bacterial strains/species and are accelerated by inappropriate antibiotic use.
• Antimicrobial stewardship is crucial to reduce the development of antibiotic resistance.

Animal Nutrition

• Digestibility refers to the ability of an animal to internalize and utilize nutrients from food.
• Energy is the baseline feed requirement, and without adequate energy, all other nutrients are wasted.
• Lysine is a crucial amino acid, and without it, the animal cannot utilize other amino acids/nutrients.
• Proteins are required for growth and are composed of amino acids, with 10 essential amino acids in dogs and 11 in cats (plus taurine).
• Limiting amino acids, such as lysine and threonine, are essential for growth, and growing animals require an even greater percentage of these amino acids per kg of body weight.
• Lipids (fats and oils) function as an energy storage mechanism, and essential fatty acids, such as arachidonic acid in cats, cannot be synthesized by the animal.

Genetics and Breeding

• Quantitative traits show continuous (numerical) expression and are influenced by multiple genes.
• Major genes have a significant influence on a quantitative trait, such as the double muscling gene.
• Breeding objective is a clear goal of selection, focused, quantifiable, and with a timeline.
• Breeding value is the value of an animal as a genetic parent, calculated as herd average + heritability (average - individual phenotype).
• Heritability measures the strength of the relationship between breeding values and phenotypic values for a trait in a population.
• Dam refers to a female parent, and sire refers to a male parent.

Animal Breeding Concepts

• Selection involves choosing the parents of the next generation to increase the frequency of desirable genes in the population.
• Natural selection occurs in nature without human intervention, while artificial selection involves human control, including replacement selection and culling.
• Index selection involves calculating a total score for each animal based on the merit in each trait, with selection indices expressed as net profit per cow mated.

Mating Systems

• Random mating involves choosing mates at random, without selection.
• Assortative mating involves mating individuals according to their phenotypes, with positive assortative mating involving similar phenotypes and negative assortative mating involving unlike phenotypes.
• Inbreeding involves mating individuals that are more closely related than the average of the population, which can uncover genes that cause defects and result in inbreeding depression.
• Outbreeding involves mating individuals that have unlike pedigrees, reducing homozygosity and increasing heterozygosity, and increasing the mean of the population.

Toxicology

• Margin of safety is calculated as the dose that is lethal in 1% of animals divided by the dose that is effective in 99% of animals (LD1/ED99).
• Toxicokinetics describes the movement and fate of toxins once they contact or enter the body, involving four primary processes: absorption, distribution, metabolism, and elimination.
• Absorption can occur through ingestion (oral route), percutaneous route (through the skin), or other routes.

Zoonoses and One Health

• Investigating a novel disease involves understanding the transmission of diseases, such as RHDV and vCJD, and implementing measures to reduce transmission and prevent outbreaks.

Thermoregulation

• Thermoregulation refers to the physiological and behavioural processes by which an animal attempts to maintain a stable internal body temperature by regulating heat gain and heat loss
• Poikilotherms are organisms whose core temperature varies considerably with the environmental temperature, and they regulate their temperature primarily through behavioural means
• Homeotherms are animals able to maintain a relatively stable internal core temperature range by internal means within a wide range of environmental/ambient temperatures
• Internal means of thermoregulation include shivering, non-shivering thermogenesis, piloerection, and skin vasoconstriction

Animal Welfare

• Animal rights are a philosophical position that animals have inherent moral rights, and animal utilisation by humans contravenes animal rights as animals should have a right to consent
• The five freedoms of animal welfare include:
• Freedom from hunger or thirst
• Freedom from discomfort
• Freedom from pain, injury or disease
• Freedom to express most normal behaviour
• Freedom from fear and distress
• The five domains of animal welfare include nutrition, environment, health, behaviour, and mental state

Toxicology

• Toxins can be absorbed through the airways, and the rate of distribution depends primarily on blood flow and the rate of diffusion out of the capillary bed and into the tissues
• Metabolism involves altering the physical properties of the toxin from those favouring absorption to those favouring excretion in the urine and faeces
• Phase 1 reactions are catabolic and involve cytochrome P450 enzymes in the liver, while Phase 2 reactions are anabolic and lead to inactive products

Epidemiology

• Inductive reasoning is looking at a situation and deducing what may come next
• Descriptive studies include case reports, case series, and surveys
• Analytical epidemiological studies include cohort, case-control, and cross-sectional studies
• Experimental studies include lab experiments and clinical trials
• The null hypothesis states that no difference exists between groups, and the aim of the study is to reject the null hypothesis and illustrate a correlation between the two groups
• Bias can be ruled out by examining the materials and methods to make sure the comparison was fair

Disease Control

• Biosecurity involves limiting vehicle entry, limiting people entry, and preventing contact with wildlife
• Vaccination and antibiotics can be used to control disease
• In-feed antibiotics can lead to the emergence and spread of antibiotic resistance via the food chain and/or a contaminated environment

Negative Impacts on Pets

• Reduces life expectancy due to secondary health issues
• Impacts quality of life
• Examples of negative impacts include:
  • Separation anxiety in dogs leading to problematic behaviors and stress
  • Health issues in flat-faced pets due to crowded dentition, skin folds, and closed airways
  • Stress and anxiety in pets trained with dominant or aversive methods
  • Repetitive behaviors in pets, potentially indicative of bigger welfare concerns

Animal Nutrition

• Macronutrients: carbohydrates, proteins, fat, and fiber
• Micronutrients: minerals and vitamins, essential for high performance and low genetic defects
• Crossbreeding: combining good traits from different breeds to improve overall performance
• Breed complementarity: crossing breeds with different but complementary biological types
• Heterosis/Hybrid Vigor: increased performance in hybrids due to genetic differences

Genomic Selection

• Looks at all genes and their interactions to influence growth and development
• Genomic testing predicts future profitability potential by identifying genetic merit
• Single nucleotide polymorphisms (SNPs) are used to identify genetic markers
• Genomic selection is a two-step process:
  1. Estimating the effects of markers in a reference population
  2. Predicting breeding values or EPDs in a test population
• Example: genotyping bull calves to select for desirable traits and reduce generation interval

Reproductive Strategies

• Artificial insemination
• MOET (surrogates carrying offspring of genetically desirable breeding pair)
• JIVET
• Sexing semen
• Cloning
• DNA collection: collecting hairs with follicle intact, alongside animal ID and sterile equipment

Genetic Defects

• Diseases or disorders inherited genetically
• Lethal genes: cause death of individual prior to or shortly after birth
• Detrimental genes: decrease vigor and vitality, but do not cause death
• Eliminating genetic defects: culling offspring and sires with defects, replacing with clean-pedigree sires

Environmentally Caused Defects

• Defects occurring due to maternal diet deficiencies or stress
• Generally gases, vapours, aerosols, or volatile liquids absorbed via the lungs

Toxin Distribution and Metabolism

• Distribution: rate depends on blood flow and diffusion into tissues
• Toxins accumulate in specific organs and tissues
• Metabolism: altering physical properties of toxins to favor excretion
• Phase 1 reactions: catabolic, forming reactive products, often involving cytochrome P450 enzymes
• Phase 2 reactions: anabolic, leading to inactive products, mostly occurring in the liver

Microbiology

• Bacteria: catabolize organic compounds, differ from viruses in structure, genome, and replication
• Obligate parasites: require a host to survive, saprophytes: can live freely
• Normal flora: always present, varying between species, with roles in health and diagnosis
• Making a microbial diagnosis: considering the presence of an organism, its role in disease, and correct sampling and examination

Parasites

• Classification: protozoa, trematodes, etc.
• Biology: free-living or parasitic, unicellular or multicellular
• Pathogenesis: intraintestinal or extraintestinal, acute or chronic
• Lifecycles: direct or indirect, asexual or sexual
• Examples: Giardia, Cryptospora, Toxoplasma, etc.

Bone Fractures and Horse Racing

• Microfractures, or minute cracks in the bone, can lead to bone weakening and are often invisible to the naked eye, requiring a microscope or high-quality bone scan to detect.

Horse Racing Industry

• Most horses retire by the age of 5, with many female horses becoming "brood mares" and remaining in the industry.
• Male racehorses, being castrated, have no role in the breeding industry and may face inadequate care or mistreatment in retirement.
• The NSW racing industry has denied sending horses to pet food abattoirs, but alternative humane management options are needed for retired horses.

Greyhound Racing

• The greyhound racing industry is smaller, with a value of $4 billion, and has its own set of welfare concerns.
• Illegal training methods, such as using live prey, are a concern, as well as the fate of greyhounds that do not go through adoption programs.
• An estimated 16,000 to 25,000 greyhounds are unaccounted for, and the industry is at risk of being banned.
• The Greyhound Risk Victoria Animal Welfare Program aims to address these concerns through rehoming, education, research, and veterinary support.

Welfare of Animal Companions

• Attitudes towards animals are shaped by community standards, personal experience, and professional opinions.
• Crossbreeding combines the good traits of different breeds, resulting in breed complementarity and heterosis/hybrid vigor.
• Genomic selection allows for more accurate animal selection and breeding decisions by analyzing genetic markers.

Genomics

• Genomics looks at the interaction of all genes to influence an organism's growth and development.
• Genomic testing can predict future profitability potential by analyzing genetic markers, such as single nucleotide polymorphisms (SNPs).
• The goal of genomic selection is to rank animals based on their genetic merit as early as possible in their life.

Bacteria and Viruses

• Bacteria can catabolize all naturally occurring organic compounds, and viruses differ from bacteria in their structural unit, genome, replication, and size.
• Obligate parasites are not able to survive independently, while saprophytes can live freely.
• Not all infectious agents cause disease, and normal flora can have a role in health, but an overgrowth can cause disease.

Microbial Diagnosis

• Making a microbial diagnosis involves detecting the organism, determining its role in the disease, and considering alternative causes.
• Sample collection, handling, and examination are critical to making an accurate diagnosis.

Parasites

• Classification of parasites includes protozoa, trematodes, cestodes, and nematodes.
• Each type of parasite has unique characteristics, such as life cycles, pathogenesis, and biology.

Disease Dynamics and Zoonoses

• Epidemiological triad classifies disease by clinical sign, syndrome, anatomical abnormality, and cause.
• Necessary causes are conditions that must be present for disease to occur, while sufficient causes are the minimal conditions required to produce disease.
• Iatrogenic transmission involves horizontal transmission through treatment or medical equipment, while zooanthroponosis refers to reverse zoonosis.

Livestock Intensification and Zoonoses

• Increasing demand for animal products in developing countries leads to livestock intensification.
• Identifying the origin of disease involves determining the pathogen, genomic sequencing, and testing for antibodies.
• Bats are effective reservoirs and transmitters of viral zoonoses due to their ability to fly and adapt to viruses.
• Examples of spillover include rabies, Ebola, Nipah, and bovine TB.

Rabies and Australian Bat Lyssavirus

• Rabies is caused by the Rabies lyssavirus, with several genotypes that may be host or geographically associated.
• The virus concentrates in animal saliva and is transmitted through contact with fresh wounds or unprotected mucous membranes.
• Signs of illness may appear within 10 days and several months, and death typically occurs within 10 days after clinical signs are present.

Explore the mechanisms of toxicity, including receptor-mediated, enzyme-related, and more, and understand how pesticides rely on selective toxicity to target specific species.