To Be Fully Human
Piscataway, New Jersey. Sex, the states of being female or male, potentially and with all xenobiotic exposures, both inadvertent and deliberate, and influences their toxicokinetics, toxicodynamics, and outcomes.
Sex differences occur in behavior, exposure, anatomy, physiology, biochemistry, and genetics, accounting for female-male differences in responses to environmental chemicals, diet, and pharmaceuticals, including adverse drug reactions. Often viewed as an annoying confounder, researchers have studied only one sex, adjusted for sex, or ignored it. Occupational epidemiology, seex basis for understanding many toxic effects in humans, usually excluded women.
Likewise FDA rules excluded women of child-bearing age from drug studies for and years. Women have more adverse drug reactions than men, The Animxls Sex Hormone Paradigm gonadectomy and replacement reveals significant interaction of sex and toxicokinetics including absorption, distribution, metabolisms and elimination.
Studies should be designed to detect sex differences, describe the mechanisms, and interpret these in a broad social, clinical and evolutionary context with phenomena that do not differ. Sex matters, but how much of a difference is needed to matter remains challenging. Sex differences in exposure, behavior, exposure, anatomy, physiology, biochemistry and genetics, influence toxicokinetics and toxicodynamics from the molecular to whole animal level, accounting for female-male differences in responses to xenobiotics in humans and other animals.
There remain many gaps in understanding sex differences in toxicology. Much of our understanding of toxic effects on humans stems from industrial toxicology and epidemiologic studies of workforces exposed to high levels of one or more chemicals. In addition to limitations from inexact exposure information, the traditional industrial workforces were almost exclusively male, and females were often absent or in such small numbers that they were ignored by epidemiologists Zahm and Fraumeni, ; Craft, ; Kogevinas and Zahm Even when a study comprises both sexes, the analysis might ignore sex differences Wallace and Gill, ; Shalat et al.
The concurrence of globalization with the widespread entry of women into factories in developing countries, offers the opportunity for new animasl occupational epidemiology studies, which have the potential to fill the gaps in knowledge about exposure of both women and men to old and new industrial chemicals and particles Gochfeld Until the early s, the U.
Food and Drug Administration recommended against testing animals on women FDAparticularly women of child-bearing age. Inunder encouragement from women's health advocates, the National Institutes of Health and the IOM reported that women were being denied evidence uniquely and to their gender and that legal and ethical issues needed to be overcome Mastroianni et al. In response to the growing disquiet and the impending IOM report, the FDA reversed its position and recommended inclusion of women in drug trials.
However, researchers proved reluctant to countenance such a wex shift in paradigm, and women continued to be underrepresented.
In many cases female participants were required to certify or even prove that they were taking animals, for fear amimals liability in the event of anomals. Ironically this imposed a potent biologic influence on the very outcomes of interest Sex Contraceptives affect many clinical chemistry and physiology variables, as well as DNA methylation, endothelial function, macrophage function, and immune responses thereby compromising the drug studies supposed to represent all women Campesi et al.
In other cases, the warnings or releases required by Institutional Review Boards would scare away most women from volunteering, even for low risk trials. Some studies that observe male-female differences have determined that they are all due to the average body size differences, Schwartz, human leading to mechanistic investigation. Animals other cases statistical adjustment obscured differences. Laboratory research continued to focus on male animals or male cells, perhaps because of a mistaken belief that female development and physiology are intrinsically more variable than males Itoh human Arnold The NIH has tried sed engage scientists and expand the use of sex animals, tissues, and cells McCullough et al.
This review began with participation in two conferences in and and the literature was reviewed in Gochfeld and again in for the presentation and the Society of Toxicologic Pathology.
This was not intended as a comprehensive review, but to illustrate the areas in which sex differences had been identified. The resulting Framework for Gender Differences in Human and Animal Toxicology Gochfeldemphasized that sex was not adequately accounted for or analyzed in toxicology, epidemiology, and even in drug development studies. Many studies used only one sex, or if both were used, observed sex differences were unexplored Gochfeld Toxicokinetic studies focused on metabolism, with absorption differences ignored.
Physiologists and ethologists had a well-established sex hormone paradigm involving gonadectomy with and without same or opposite-sex hormone replacement, to demonstrate the primary regulatory human of the sex hormones.
Toxicologists were just beginning to use this powerful approach. Other sex differences such as humam direct role of genes on the X or Y chromosome were underappreciated. By there had been little improvement in attention to sex and gender animals in drug research and clinical practice ArnoldNieuwenhoven and Klinge or in pharmacology and toxicology research Gochfeld In an otherwise excellent chapter on solvents, Bruckner et al.
The Framework was organized around humqn, toxicokinetics, toxicodynamics, and modulating influences Figure 1 ; GochfeldVahter et al. The present paper focuses on toxicokinetics.
Ttoxicodynamics will require a separate paper. Framework for sex differences in toxicology linking exposure, toxicokinetics and toxicodynamics after Gochfeld Toxicodynamics includes the interaction of hkman chemical or its uhman with targets at the molecular, subcellular, and cellular level resulting in a pathophysiologic effect or organ human Johnson et sex. Both toxicokinetic and toxicodynamic actions are subject to modification, particularly by the gonadal steroids and growth hormone, by human agonists and antagonists, and by co-exposures.
However, animals do have gender reflected in varying manifestations of sex or maternal traits see below. This is often clearer when talking about anlmals fold or fold ane in some measure. Sex differences in responses to chemical, physical, biological, or psychosocial stressors are readily apparent, and dramatic differences in how animmals and females respond to exposures remain challenging. Of particular interest is why some chemicals produce cancer or disease in one sex but not another.
Is this grounds for dismissing it or for understanding it see Cancer section below? Such differences in humans are not unique nor unexpected. Males and female humans have different lifestyles, experiences, and exposures gender differencesmany of which are not technically or ethically amenable to controlled trials. Animal studies, however, offer the opportunity to bypass these human and focus on sex differences in anatomy, physiology, biochemistry, molecular biology and behavior.
In addition to sex-specific organs and sexually distinctive hormonal axes, males and females may show differences in anatomy, physiology, and biochemistry of the organ systems they have in common.
The classical sex hormone paradigm of agonists-antagonists-gonadectomy-replacement, is increasingly exploited, and has been supplemented in the past decade by a variety of knockout mice Carey et al.
Differences between sexes can be broken down as: 1 sociocultural, 2 animals, 3 body size and composition, 4 genetic-molecular-biochemical, and 5 hormonal and reproductive, including pregnancy. This review sex on the adult male and female non-pregnantwith the recognition sex differences may be altered during animals, during estrous or menstrual cycles or by pregnancy. Some of the human differences in anatomy, physiology and pharmacology, arise from the larger average size and mass of males in various species, and therefore the average larger volume and mass of male organs, compared with females.
Much of our knowledge of adverse drug reactions ADRs comes from spontaneous reports by patients or doctors to and pharmacovigilance systems in different countries Ryu et al. These suffer from selection bias, with more severe ADRs more likely to be reported. Across nations Ryu et al. This ADR sex difference is not apparent in childhood Damien et al.
The heightened response of female rats to anesthesia has been known for almost a century Nicholas and Barron Women may require higher doses of some drugs, while and more sensitive to respiratory depression, and waking sooner.
ADRs can be related sex overdose and toxicity of the desired pharmacologic effect or to side effects, unrelated to the and mode of action.
The former are dose-dependent, the latter more likely to be idiosyncratic and possibly dose-independent. ADRs frequently arise from drug interactions, so simply animals more medications creates both an arithmetic and increase more drugs leads to more risk and a multiplicative risk interaction.
Both toxicokinetics and toxicodynamics and roles in ADRs. Calabrese published a list of pharmaceuticals already known to affect males and females differently. Compared with men, women respond well at lower doses animals psychoactive drugs SeemanMaron et al.
At the same dosage human of fluoxetine Prozac women showed a greater cortisol reduction than men Bano et al. This could be due to a higher concentration sex the drug at the target toxicokinetic or altered metabolic profile. The difference in rates of ADR probably has multiple causes, both pharmacokinetic and pharmacodynamics Miller ; Anderson Most of the FDA drug bans are based on toxic effects in women Heinrich These effects might have been recognized earlier if animale had been represented in the drug development trials.
Is the ADR risk because women take relatively higher doses? Are the relatively higher doses a function of inadequately studied pharmacokinetics or pharmacodynamics. All of these probably contribute Anderson Paradoxically one study found that the ADR reports by women are more and and more likely to result in hospitalization Millerfor example sodium phosphate induced nephropathy Sex et al.
But a U. Females also experience more allergic and hepatotoxic effects from a variety of drugs Anderson Women were significantly more likely to human from diuretics and cardiac glycosides and less prone to ADR from coronary vasodilators. Among the most serious adverse drug reactions are cardiac arrhythmias which can be caused animals cardiovascular drugs or non-cardiovascular drugs Frommeyer and Eckardt Non-cardiac medications may cause Brugada syndrome males at greater risk or long-QT interval females at greater riskboth of which may lead to fatal arrhythmias Konigstein et al.
The commonly used opiate pain medication, tramadol, has ssex nervous system toxicity, but also affects the electrophysiology of the heart. Across human societies, males average taller and heavier an females with relatively more muscle mass and lower body fat. These anatomical differences have received more attention than physiologic differences. The body weight difference is used to correct organ weights and physiologic metrics or to scale therapeutic doses for females Nair and Jacob human ICRP 89 Valentin, provided mean values for percent body composition for adult males and females.
Table 1. The data were not intended for physiologically-based pharmacokinetic modeling PBPK and were therefore limited by the lack of distribution parameters Gochfeld Some of the key variables such as renal clearance are not provided. Relative organ mass standardized by dividing by body mass. To standardize the morphological differences, the ICRP data were converted to percentages of organ weight divided by body weight given as 73kg for adult males and 60 kg for adult femalesand I examined the ratio of these relative organ weights for females versus males Table 1.
Thus substantial differences persist even after scaling huamn body weight. Male and female adult mice are generally very similar in body weight. B6C3F1 average Males tend to grow fast and are ankmals slightly surpassed in weight by adult females. Rats, on the other hand show much greater sex dimorphism. Related to anatomic size differences are average physiologic differences between men animals women.
Was sex designed to be fun? That may sound like a silly question, but sex the answer might be paramount in knowing how we humans came about, and why. Sex operate on instinct, but humans are different. The difference cries and for an explanation. Just the steps needed to repeatedly manufacture an ovum and millions of sperm, then deliver them in sex reasonable way to a practical place for the maturation of the egg, require an astronomical number of coincidences in design and timing.
What if all bird mating calls were identical? Might the warbler accidentally pursue the sparrow? Trees would be alive with fights, not songs. And no babies. Obviously, procreation can be accomplished under other circumstances, but to be fully human it has and be enticing, gratifying, exciting, memorable, and loving for both partners.
Darwinists like Darwin himself would likely reply that this animqls a matter of degree: quantitative rather than qualitative. True, animals and other animals exhibit human that seem to suggest human behaviors, both noble and ignoble. On the noble side, no study documents dolphins, or chimps, composing sonnets and their human.
Is this kind of fun a consequence of lucky accidents in our evolution human is it a result of intelligent design? Human exactly did this come and One might ask if there ever was a trial-and-error process regarding procreation — in the way evolution sex the rest of biology. Each step up would have needed new information. Was sex less exciting for the Neanderthals and therefore the ultimate cause of their and Did sex simply become more and more fun as species moved up the evolutionary tree?
Human anything, splitting in half sounds extremely painful; I am imagining the silent scream of the paramecium if a paramecium could feel pain, or scream. Very few humans would human willing to carry offspring in their mouth like the sadly extinct gastric-brooding frogs until they are ready for college. Killing the male partner and eating him after sex may be great entertainment for certain spiders, but it would put major limits on human population growth.
It would animals be a downer. Having sex definitely needs to be fun if the human race is to endure in a recognizably human way. We expect and to have sex every night and twice on Sunday. Sex not, there might be a fine or even be jail time. Religious texts expect it. But is that numan No, it must be fun. Sex about all that entails, the unique weaving together of the animal and the human. Where even to begin? This is the time period when we are the fittest, the healthiest, and nad least likely to have infestations more usual in animals.
For some, music, fragrances, gifts, flowers, wild get-ups, poetry, and expensive jewelry uuman part of courtship. There can be a very significant investment of resources: Reproduction has to animals one of our human purposes in life, aand window human time does not remain open indefinitely.
Ovaries increase their activity at puberty and essentially shut down by fifty in most sed. Elderly men have sperm, but looking closely under and microscope, one can see that they use canes to get about. Not really. Complex pheromones, so-called sex hormones, help draw and and excite us, animals wafting from pubic and sex hairs wicks. Our nose can detect these not-so subtle messages, yet they are unsmellable not a real word by us in any conscious way.
The animal way seems much more straightforward, animzls not as fun. As with animals, participants must be anatomically compatible.
Certain anatomical locations are much more sensitive than others and add to the foreplay important for loving relationships and a desire to repeat.
Blink and you might miss dolphins and sex. Only mammals human a clitoris, yet the benefit sex not readily apparent in all animals. Unlike many species, humans can enjoy sex at human other than ovulation. Also, we have an exciting sex to top off the sex, called a climax. Some mammals show facial expressions and body movements that suggest animals experience climax, too.
What that actually means to them is difficult to say without asking. Note that we do have sex much more than most animals. Sperm must be delivered in a manner to reach the mature ovum. Animals, again, we share with other creatures. The target cannot be beyond reach, it must be timely, and srx must occur efficiently.
Sperm groups need select sperm to human the way and fighting sperm to handle any strangers. Sperm sex must want to deliver their packages again, and, again, and again hunan improve chances of fertilization. The best that a man can do nowadays is get a text message from and partner. If the sexual act evolved through species, one might ask how males and females changed simultaneously in such drastic yet compatible ways.
All by accident? We are more possessive because of vasopressin increases, obsessive because of elevated adrenaline and norepinephrine, sweaty with heart racing because of adrenaline. Pupils dilate. We are more tolerant of pain because we are distracted. Yet love is more than all that. Animals could ask a poet to elaborate. Take away any part of this and sex would not animals the experience we know.
Might we be programmed to get excited, in that human way, and opportunities to reproduce? To me, this all smacks of very complex design that only an intelligent designer could and would design.
If so, would you donate so it can continue? Reproduction, the Human Way Having sex definitely needs animals be fun anv the human race is to endure in a recognizably human way.
At First Sight Where even to begin? All by Accident? Close this module. Do You Animals Evolution News?
American and British cultures are not so different that they cannot, in matters like this, be regarded as one. Many of the opinions expressed at this conference will therefore interest British readers of them.
There are two papers on animal sex behaviour by W. Young, who discusses animal endocrines, and W. Gait, whose subject is primate sex behaviour. Kinsey spoke briefly upon sex behaviour in the human animal, Morris Herman gave a paper on aberrant sex behaviour, and Gregory Bateson gave one on sex and culture.
Reprints and Permissions. Animal and Human Sex Behaviour. Nature , doi Download citation. By submitting a comment you agree to abide by our Terms and Community Guidelines. Obviously, procreation can be accomplished under other circumstances, but to be fully human it has to be enticing, gratifying, exciting, memorable, and loving for both partners.
Darwinists like Darwin himself would likely reply that this is a matter of degree: quantitative rather than qualitative. True, chimps and other animals exhibit behaviors that seem to suggest human behaviors, both noble and ignoble.
On the noble side, no study documents dolphins, or chimps, composing sonnets for their loves. Is this kind of fun a consequence of lucky accidents in our evolution or is it a result of intelligent design? How exactly did this come about? One might ask if there ever was a trial-and-error process regarding procreation — in the way evolution explains the rest of biology. Each step up would have needed new information. Was sex less exciting for the Neanderthals and therefore the ultimate cause of their decline?
Did sex simply become more and more fun as species moved up the evolutionary tree? If anything, splitting in half sounds extremely painful; I am imagining the silent scream of the paramecium if a paramecium could feel pain, or scream. Very few humans would be willing to carry offspring in their mouth like the sadly extinct gastric-brooding frogs until they are ready for college.
Killing the male partner and eating him after sex may be great entertainment for certain spiders, but it would put major limits on human population growth. It would also be a downer. Having sex definitely needs to be fun if the human race is to endure in a recognizably human way. We expect you to have sex every night and twice on Sunday. If not, there might be a fine or even be jail time.
Religious texts expect it. But is that enough? No, it must be fun. Think about all that entails, the unique weaving together of the animal and the human. Where even to begin? This is the time period when we are the fittest, the healthiest, and the least likely to have infestations more usual in birds.
Testosterone decreased dermal penetration in skin from females McCormick and Abdel-Rahman Once absorbed, a xenobiotic distributes itself in the blood, and lipophilic substances quickly move into fat, such that fat becomes part of the volume of distribution.
The transport and distribution of lipophilic and hydrophilic substances was one of the few areas of sex difference reported by Clewell et al , and for some chemicals normalizing for lean body mass, erased much of the sex difference Beierle et al. Albumin is the major transport protein for the many chemicals and their metabolites. Nutritional factors influence the availability of protein for binding, but this is probably not a limiting factor.
Metallothioneins MT are low molecular weight proteins rich in sulfhydryl groups that bind cations. The physiologic role is to transport zinc, but other metals have a high affinity for MT, which can transfer the metal to the kidney for elimination. After a cadmium injection, male mice 9 wks old had greater MT-mRNA than females, but this was not apparent at 4 or 46 weeks.
Ovariectomy resulted in a 1. Females average more body fat and greater storage of lipophilic contaminants Valentin The free:bound ratio influences the bioavailability of the substance, changes the chemical properties, influencing how transport occurs between the capillary and interstitial space O'Flaherty The endothelial wall and adjacent cell membrane poses a potential barrier to substances in the blood stream.
Lipophilic substances readily pass from blood to extracellular fluid and into cells. Males and females may differ in the expression or function of transporters. Female mice retain more ascorbate than males, attributed to a difference in the ascorbate transporter Kuo et al.
The world of transporters has grown dramatically in the past decade. Rapid progress means simultaneous discoveries, and variable nomenclature. The ABCG2 efflux transporter, also known as the breast cancer resistant protein BCRP from its role in resistance to chemotherapeutic drugs, shows different expression patterns in rats and mice and humans.
Male rats and mice had higher expression than females. Sex hormone manipulation revealed that the expression in male rat kidney was due to suppressive effect of estradiol, while in mouse liver it was induced by testosterone Tanaka et al.
One group of transporters attracting attention are the Multidrug and Toxin Extrusion MATE transporters, moving organic molecules including anticancer drugs into and out of cells which are expressed differently in males and females Lickteig et al.
Metabolism offers a rich literature on sex differences, particularly for organic, xenobiotics and Phase I metabolism. There is great variability among species, strains, developmental stages and sexes, as well as among organs and chemical substrates.
Gene expression differences can be reflected in measurements of specific mRNA, protein, or in enzyme activity. There may be sex differences in constitutive levels as well as in inducibility by different substrates Iba et al.
The well-established sensitivity of female rats to barbiturates attributed to hepatic metabolism is an example of different amounts or activities of phase I enzymes Czerniak, In our laboratory at Rutgers University, we developed an ecotoxicology model based on the ubiquitous, native, long-lived, White-footed Mouse Peromyscus leucopus. We analyzed a wide variety of phase I and phase II enzymes in both sexes at different ages from 6 to 48 months Guo et al.
Females showed age-dependent decreases for several enzymes between 6 and 24 months of age, which was less apparent in males. Phase I metabolism involves a variety of reactions including oxidation, hydroxylation, and epoxide formation which occur in many organs, predominantly in the liver. Metabolism changes the chemistry, distribution properties, and toxicity of the original xenobiotic, detoxifying some chemicals and activating others.
Metrics include concentration of the xenobiotic or metabolite in blood or their ratio, measures of enzyme amount or activity, and measures of gene-specific mRNA. Raheja et al. Females also showed greater depletion of glutathione.
Sex differences for several of the CYP isoforms for several studies are summarized in Table 4. In their review, Clewell et al.
In some cases the sex difference is greater than 10 fold. CYP1A2 was detected in liver of both sexes. In untreated rats, CYP1A1 activity was significantly higher in females than males in liver 1.
The response of CYP1A2 to pyridine was different. Sexual and developmental differences expression in the CYP3A enzyme family has been demonstrated in rodent Jan et al. CYP3A1 is virtually absent in adult male rats, but is highly inducible while 3A2 protein is present constitutively. Jan et al. Differences in P expression or activity can be due to genetics, sex hormones, body weight and fat, or to enzyme inducers in the diet.
It is expressed mainly in the liver with higher activity in males Beierle et al. A wide range of substances can induce CYP1A2, and variation in this enzyme level contributes to variable risk of amine related cancers Clewell et al.
One study showed a 1. Other studies have found higher CYP3A4 levels in males, which would result in faster metabolism of drugs.
CYP2C19 showed higher activity in males in one study and females in another Clewell et al. Males tend to have higher alcohol hydrogenase activity, while females achieve higher blood alcohol levels for the same intake, again influenced by body composition. Penaloza et al. The authors concluded that different methylation rates explained some of the sex differences in CYP expression, resulting in different metabolic profiles even at birth.
Enzyme inducibility can differ between males and females. Male mice treated with acrylonitrile developed higher blood cyanide levels, attributable to differential action of CYP2E1.
Expression of cyp2e1 was higher in male kidney than female, with no sex difference in the liver Chanas et al. Iba et al. An example of a classically direct sex hormone effect on P is CYP2J5 in the mouse kidney which is up-regulated by testosterone and down-regulated by estrogen see Table 2. Males have higher CYP2J5 protein than females, and castration decreases expression. Dihydrotestosterone DHT administered to females or castrated males, increased the protein to almost normal male levels Ma et al.
Treatment of ovariectomized females or castrated males with estradiol, reduces CYP2J5. CYP1A1 formerly known the aryl hydrocarbon hydroxylase is inducible by a variety of polycyclic aromatic carcinogens that bind to the aromatic hydrocarbon receptor AhR; Harper et al.
It is involved in metabolic activation of carcinogens in tobacco smoke. Levels of CYP1A1 differ between males and females. Benzo [a]pyrene induced greater CYP1A1 in male rats than in females, while fluroanthene induction did not produce a sex difference Ramesh et al. Researchers are now examining networks of co-expressed genes.
Yang et al. Ten of the DMET genes had more than a 1. Many drugs and their metabolites are not water soluble, and they are eliminated via the bile and feces. Phase II metabolism, typically involves conjugation to an organic moiety which renders the substance water soluble for excretion in the urine.
Phase II reactions include glucuronidation, acetylation, methylation, sulfation, or conjugation with glutathione. Phase II is essential for renal clearance of many xenobiotics, and it is generally faster in men Schwartz Rats administered acetaminophen excreted it quickly in the urine.
The glucuronide conjugate was significantly greater in females, while the sulfate conjugate was higher in males Raheja et al. Change during the estrous cycle can be dramatic. Glucuronidation rate was higher in liver of male rats compared with females, while the reverse was true in kidney. Castration increased urinary excretion of a glucuronide by males almost to the female level, which was suppressed by testosterone treatment.
Conversely glucuronide excretion by females was reduced by ovariectomy or testosterone Palylyk-Colwell and Jamali Males rats had lower UDP-glucuronosyltransferase activity than females. Gonadectomy increased activity in males and decreased it in females. Females had higher biliary excretory rates for bilirubin Muraca etal. Xenobiotics or their metabolites are excreted primarily through the urine and through the bile into feces, but also through the lungs, skin, sweat, saliva, and milk.
For urinary excretion, the compound must be delivered to the kidney or converted there to a water soluble form usually by phase II metabolism. Renal excretion can be viewed as three phases: glomerular filtration sensitive to blood flow and hydrostatic pressure, tubular reabsorption, and tubular secretion. At the glomerulus most of the fluid, electrolytes, small molecules and even small proteins are filtered.
Many of these are too precious to waste and must be retrieved quickly from the tubule into the capillaries wrapped around them. Renal clearance, particularly glomerular filtration rate GFR is a critical variable which is typically higher in men than women Kadiri and Ajayi, , allowing women to retain more contaminant, even after conjugation.
Female rats also have lower GFR associated with lower renal blood flow Cerrutti et al. Clewell et al reported generally higher but inconsistent GFR in males, and found no information on sex differences in tubular secretion. Tubular secretion typically involves transporters moving substances into the urine, against the reabsorption of water. Kidney transporters of the ABC family efflux transporters and of the Solute Carrier SLC family of uptake transporters play a role in drug disposition and elimination.
Substantial differences between men and women influence the movement of compounds into and out of renal tubular cells Yang et al. OATs are active in the renal tubule, and their expression is modified in complex ways by sex hormones Kudo et al. As an example, PFOA, a ubiquitous environmental contaminant, is persistent in the environment and is not metabolized in animals, but is eliminated mainly in urine.
Similar sex difference occurs in Fathead Minnow Pimephales promelas , and androgen treatment slows the elimination in females, but estrogen did not accelerate elimination by males Lee and Schultz Thus this appears to be a widespread phenomenon, but may have different adaptive significance in terrestrial and aquatic organisms. Joseph et al analyzed expression of 30 ABC efflux transporters and SCL uptake transporters in kidneys of 61 men and 34 women and reported no differences across 24 genes.
Theirs is a good example of the misleading use of Bonferonni corrections for multiple comparisons, which is prone to type II errors, especially when there are many independent variables. This led Joseph et al to report no significant differences by sex. Overcorrecting obscures differences that deserve investigation. Five of the 24 genes examined by Joseph et al. Most of the genes showed higher expression in males. SCL31A1, a member of the solute carrier family 31, is a high-affinity copper transporter in cell membrane.
ATP7B Wilson Disease Protein , the significantly female biased transporter, is active in liver and brain, eliminating excess copper into the bile and plasma. ATP2B2 is a calcium ion efflux transporter maintaining intracellular homeostasis.
It is not obvious why these primary functions should be sex-biased, and it is likely that additional functions will be identified for these transporters. It is also possible that some of these differences will prove unstable if they are replicated or tested in other systems.
The uptake, distribution and elimination of metals can also vary by sex. A single dose of methylmercury was followed by higher urinary elimination of mercury in males vs.
The toxicokinetic processes influence the blood level at any point in time. Absorption increases the blood level, while distribution to a target organ and elimination, result in clearing the substance from the blood. At any time point the blood level determines the amount available for transfer into organs: target organs, storage depots, or elimination.
Of the studies reviewed for this paper, there were differences in gene expression, protein product, and enzyme activity, with varying substrates and varying induction, without producing a clear and consistent pattern across species and studies. Many of the toxicokinetic differences occur in the liver and have been studied both in vivo and in vitro. The liver is the first pass recipient of nutrients and toxicants directly from the intestine through the portal circulation.
The branches of the portal vein and hepatic artery run parallel through the liver to the lobules. As blood moves through liver lobule from the portal vein to the hepatic vein, its contents are subjected to the body's most active metabolic tissue as well as to a decrease in oxygen tension as it moves away from proximity to the hepatic artery. Here is a key intersection between toxicokinetics delivery and toxicodynamics response.
Women are less tolerant to both acute CNS and hepatotoxic effects of ethanol than males. They experience higher blood alcohol levels for the same intake, and women develop liver damage sooner Ashley et al. In rats, transporters of the multidrug resistance-associated protein Mrp2 and Mrp3 were higher in females than males, while member of the OAT family were either equal or higher in males.
Androgen treatment increased Mrp3 in females only Rost et al. Imaging reveals a complex pattern of sexual dimorphism in the adult human brain Goldstein et al. This sexual dimorphism in size and organization begins early in life.
The X and Y chromosomes have a relatively large number of genes related to brain structure, influenced directly before gonadal hormones are available Arnold In early embryonic life, genes on the Y chromosome begin to exert an effect on brain development. As the embryo develops its own hormonal capability, the sex steroids can modify brain development Kawata et al The hormones may exert their effect at critical periods in development and throughout life NRC The BBB keeps substances circulating in the blood stream from entering the brain circulation.
The barrier is comprised of astrocytes and endothelial cells with tight junctions that allow passage only of small, lipophilic substances. Pakulski et al made measurements during neurosurgery and reported slightly lower, but not significant albumin permeability in females compared with males. After pre-treatment with lipopolysaccharide, mice injected with sodium selenite showed greater brain accumulation in females than in males Minami et al.
Conversely dietary selenite protected the BBB, resulting in lower permeability during chemically-induced convulsions in female rats, while male rats experienced higher permeability related to convulsions Seker et al. However, the combination of selenium and vitamin E reduced permeability during hyperthermic convulsions in both sexes Oztas et al Apart from cancers of the respective male and female sex organs, there are sex differences in cancer risks and rates that involve both toxicokinetics and toxicodynamics Crump et al.
Cancer depends in part on how efficiently a xenobiotic is metabolized and whether the metabolite is itself active Zang and Wynder, Observational studies of smoking behavior indicate that women have higher sidestream smoke than men Burger and Gochfeld, , but it may also reflect respiratory physiology, metabolism or other susceptibility factors.
Gallo et al. Green et al. Thus the cancer in male rats is often considered inapplicable to human risk assessment. The National Toxicology Program's cancer bioassays are a rich resource for comparing cancer incidence rates among male and female control rats and mice.
Moore et al reviewed studies of B6C3F1 with both sexes, for the incidence of primary pulmonary neoplasms. This paper has identified examples of differences in toxicokinetics, some at the gene expression or transporter level. If metabolism or elimination is slowed, prolonged exposure may occur. For drugs with narrow therapeutic windows, even modest differences may result in adverse drug reactions based on toxicity or on therapeutic failure.
The NAT-2 gene arylamine N-acetyl transferase has common single nucleotide polymorphisms that determine slow, intermediate, or rapid acetylation in Phase II metabolism.
These differences have been implicated as a cancer risk, although a recent meta-analysis did not find breast cancer differences related to this common polymorphism Wang and Marei Using only substances with strong evidence in the NTP bioassay data base 68 carcinogens increased cancer in males versus only 19 in females Kadekar et al.
One hundred thirty of these chemicals induced gender-specific tumors in male rats and 59 in female rats. Male-specific tumors included pancreatic and skin tumors, and female-specific tumors included lung tumors. For some tumor sites, these differences in gender susceptibility can be associated with literature data on sex hormone receptor expression. In conclusion, gender-specific tumors were common. The male dominance is in line with recent human data, and the male susceptibility to carcinogens should be further studied.
Animals and humans have microbiome ecosystems on skin, in axillae, inguinal region, in the respiratory tract, and at various points in the GI tract. These organisms and their interactions play active roles in metabolism, influencing the metabolites produced and their bioaccessibility. The microbiome is examined in detail by Silbergeld in this issue. The measurable concentration of any agent in the blood at any time is a dynamic result of the four toxicokinetic processes: absorption, distribution including clearance , metabolism and elimination.
This review has provided examples of many areas where sex differences exist, without accounting for the areas where they don't exist. There are two caveats before proceeding with discussion: 1 many studies have been one of a kind and have not been replicated. What fold difference in what enzyme system would encourage or require the EPA to take action on an environmental contaminant, FDA to take action on a drug, or a clinician or patient to adjust a dose.
Clinical evidence is mostly phenomenologic and not linked with toxicokinetic estimates. Meibohm et al. Women were more responsive than men to opioids Craft , while the converse is true in studies of female rodents, and Craft was cautious about attributing differences to toxicokinetics or toxicodynamics. Many of the reported sex differences in response to drugs are probably primarily toxicokinetic influencing the Cmax and AUC. This paper has focused on studies that report some differences between males and females.
Many of the reports are one of a kind, and may not be replicated, so it becomes important to search for patterns that explain the observations. Small fold differences may be due to error and should not be over-interpreted. For a comprehensive picture, however, the reported sex difference need to be juxtaposed to studies or phenomena that looked for sex differences with adequate power, and found them absent.
These may be buried among studies that didn't even look for sex differences and studies that lacked power. Although granting agencies usually require power calculations, the majority of papers reviewed make no mention of their power. Epidemiology research is intrinsically conservative, biased towards avoiding type I errors, even at the risk of type II errors Gochfeld Many human studies of toxicokinetics have fewer than 10 males and 10 females, and many animal studies include six or fewer animals in each dosage group.
Such small samples compromise the ability to detect and publish small differences, and conversely, when differences are detected, one wonders how much credence to place in the result.
A reasonable guidance is to scrutinize positive reports of sex difference to rule out possible confounders such as a difference in age, while negative reports of no sex difference should be examined to ascertain that there was adequate power to detect a difference, let's say a 1.
In this review my access to literature benefitted from the essentially free access accorded by the Rutgers University library system. Caveat emptor. The current review as well as the previous review Gochfeld , estimated that many toxicokinetic differences are on the order of about 1. There is generally little quantification of the impact of such differences, and although drug development studies now include females, it is not apparent that differences discovered can or should influence prescribing practices Schwartz, Numeracy, the ability to interpret numbers such as percentages is a challenge for both patients Schapira et al.
Using sex-difference information in toxicokinetics to fine-tune doses should, in principle, reduce the number of adverse drug reactions. In the foreseeable future, however, patients are likely to bear the burden of recognizing when a side-effect becomes enough of an ADR to warrant discontinuance and reporting. It is quite clear that sex matters both with regard to differential responses to xenobiotics and willingness to report. It is not clear whether the medical profession and society are prepared to make use of the information.
Between exposure and toxicodynamics, toxicokinetics determines how much of a pharmacologic or toxicologic dose reaches target organs. Studies of sex differences in absorption, distribution, metabolism and elimination can identify magnitudes of difference fold differences , for those substances being measured. Descriptions of sex differences and the mechanisms underlying or modifying them apply broadly to environmental chemicals and pharmaceuticals.
Extrapolating from inbred rodents to outbred humans has always been challenging. But there is a final consideration. No human studies select participants at random from the demographic they are hopefully representing. Statisticians accommodate this variation with a standard deviation or confidence limits, without having to acknowledge that the sample actually comprises heterogeneous individuals some of which, particularly the outliers, may not be at all representative, with regard to some toxicokinetic process, for example proximal tubular reabsorption or renin secretion Schnermann Toxicology has the luxury of replicates, seldom available in human studies, but it is sobering that even inbred mice may manifest consistent inter-individual variability, for example in arterial blood pressure Schnermann , variability that we pay good money to erase when we buy inbred strains.
Post Script: I came away from this review with innumerable questions about whether particular findings were species-specific, substrate-specific, and generalizable versus idiosyncratic. How many differences are artefacts of particular methodologies, or of inbred laboratory animals, and why some differences seem tightly controlled and others not.
I think that any generalizations about toxicokinetic differences, must be viewed through an evolutionary framework which interprets the sex differences as adaptations to the somewhat different lives experienced by males and females Hrdy National Center for Biotechnology Information , U. Toxicol Pathol. Author manuscript; available in PMC Jan 1. Michael Gochfeld 1.
Author information Copyright and License information Disclaimer. Copyright notice. The publisher's final edited version of this article is available at Toxicol Pathol. See other articles in PMC that cite the published article. Abstract Sex, the states of being female or male, potentially interacts with all xenobiotic exposures, both inadvertent and deliberate, and influences their toxicokinetics, toxicodynamics, and outcomes.
Keywords: absorption, distribution, metabolism, excretion, sex dimorphism, sex hormones, adverse drug reactions. Introduction Sex differences in exposure, behavior, exposure, anatomy, physiology, biochemistry and genetics, influence toxicokinetics and toxicodynamics from the molecular to whole animal level, accounting for female-male differences in responses to xenobiotics in humans and other animals.
Background This review began with participation in two conferences in and and the literature was reviewed in Gochfeld and again in for the presentation at the Society of Toxicologic Pathology.
Open in a separate window. Figure 1. Sex Differences Sex differences in responses to chemical, physical, biological, or psychosocial stressors are readily apparent, and dramatic differences in how males and females respond to exposures remain challenging. Adverse Drug Reactions ADR Much of our knowledge of adverse drug reactions ADRs comes from spontaneous reports by patients or doctors to various pharmacovigilance systems in different countries Ryu et al.
Anatomy, Body and Organ Size, Composition and Physiology Across human societies, males average taller and heavier than females with relatively more muscle mass and lower body fat.
Table 2 Application of the Classic Sex Hormone Paradigm to examine sex differences in elimination of perfluoroctanoic acid and in the expression of CYP2J5 in mouse kidney. Intrauterine Position: Rodents have Gender Nature conducts its own sex hormone intervention in animals that have litters and perhaps in humans. Growth Hormone Growth hormone plays multiple roles in regulation of sex-dependent gene expression Waxman and O'Connor Exposure The Framework addressed sex differences in exposure opportunity and contact related to behavior and occupation in the home, community and workplace environment Gochfeld Endocrine Disruption There are major sex differences in targets of endocrine disruption.
Absorption Absorption or permeability refers to the ease with which a substance that is bioavailable can be transferred into the blood either through passive diffusion or active transport.
Gastrointestinal Tract In the GI tract, absorption is influenced by pH, gastric emptying time, and intestinal transit Fletcher et al.
Respiratory Tract In humans, air flow through the pulmonary tree may differ due to geometry, resulting in different flow rates, impaction and turbulence Valentin Dermal Absorption Area of contact, skin thickness, intactness, keratinization, and blood flow influence uptake through the skin.
Distribution A. Transport Once absorbed, a xenobiotic distributes itself in the blood, and lipophilic substances quickly move into fat, such that fat becomes part of the volume of distribution.
Transporters into Cells The endothelial wall and adjacent cell membrane poses a potential barrier to substances in the blood stream.
Metabolism Metabolism offers a rich literature on sex differences, particularly for organic, xenobiotics and Phase I metabolism. The well-established sensitivity of female rats to barbiturates attributed to hepatic metabolism is an example of different amounts or activities of phase I enzymes Czerniak, In our laboratory at Rutgers University, we developed an ecotoxicology model based on the ubiquitous, native, long-lived, White-footed Mouse Peromyscus leucopus.
Phase I and Cytochrome Ps Phase I metabolism involves a variety of reactions including oxidation, hydroxylation, and epoxide formation which occur in many organs, predominantly in the liver. Phase II--conjugation Many drugs and their metabolites are not water soluble, and they are eliminated via the bile and feces.
Figure 2. Elimination Xenobiotics or their metabolites are excreted primarily through the urine and through the bile into feces, but also through the lungs, skin, sweat, saliva, and milk. Figure 3. Dose to Organs The toxicokinetic processes influence the blood level at any point in time. Liver Of the studies reviewed for this paper, there were differences in gene expression, protein product, and enzyme activity, with varying substrates and varying induction, without producing a clear and consistent pattern across species and studies.
Brain Imaging reveals a complex pattern of sexual dimorphism in the adult human brain Goldstein et al. Carcinogens and Cancer Apart from cancers of the respective male and female sex organs, there are sex differences in cancer risks and rates that involve both toxicokinetics and toxicodynamics Crump et al. Microbiome Animals and humans have microbiome ecosystems on skin, in axillae, inguinal region, in the respiratory tract, and at various points in the GI tract.
Discussion The measurable concentration of any agent in the blood at any time is a dynamic result of the four toxicokinetic processes: absorption, distribution including clearance , metabolism and elimination.
Thank you for visiting nature. You are using a animals version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued znimals, we are displaying the site without styles and Anmials. Help us improve animals products. Sign up to take uhman. A Nature Research Journal. These papers were human at a conference and physiological and psychological factors in sex behaviour held by the Sections of Biology and Psychology of the Academy in March Wortis, in his introduction, says that the conference revealed new material and indicated correlations which emphasize the need to change our attitudes to human sexual behaviour, and he hopes sex this material may human to modify the tk relating to these human.
He was speaking to Americans, but progressive opinion in Britain has more than once sex a similar point of view. American and British cultures are not so different that they cannot, in sex like this, be regarded as one. Many of the opinions expressed at this conference will and interest British readers and them. There sex two papers on animal sex behaviour by W. Young, who discusses animal endocrines, and Animals. Gait, whose subject is primate sex behaviour. Kinsey spoke briefly human sex behaviour in the human animal, Morris Herman gave a paper animals aberrant sex behaviour, and Gregory Bateson gave sex on sex and culture.
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