Ronald A. Kahn, MD

These particles respond strongly to an external magnetic field but have no permanent magnetic moment in the absence of the field because thermal energy is sufficient to cause fluctuations in the small magnetic dipole associated with each particle (Cole et al erectile dysfunction doctors in south africa order adcirca on line. Nanomaterials can enter target cells by passive diffusion viagra causes erectile dysfunction purchase genuine adcirca, direct physical penetration erectile dysfunction treatment options injections purchase adcirca 20 mg with mastercard, or active erectile dysfunction zinc buy line adcirca, receptormediated uptake by endocytosis or phagocytosis depending on their size and extent of agglomeration male erectile dysfunction pills review buy adcirca 20 mg cheap. Rigid, long, high aspect ratio nanomaterials, similar to amphibole asbestos fibers (Palomaki et al. Biopersistence is related to dissolution, which not only produces biologically active ionic species (as discussed above), but can also degrade the particle and eventually clear it from biological tissue or the natural environment. The rate of dissolution of metal oxides is increased by natural organic matter in the aequous environment (Xia et al. Intracellular release of Zn2+ or Ni2+ ions, for example, is linked with significant acute toxicity to target cells in the lungs (Xia et al. In contrast, carbon nanomaterials are potentially biodurable raising concern that they could bioaccumulate in the environment or be biopersistent in the lungs and other organs following inhalation during occupational exposure or direct injection or implantation in biomedical applications (Bianco et al. Biopersistence in the lungs and pleural or peritoneal spaces is an important physicochemical characteristic of asbestos and man-made mineral fibers associated with carcinogenicity (Bernstein et al. Graphene oxide nanosheets have also been shown to be degraded in the presence of horseradish peroxidase and H2O2 (Kotchey et al. The interaction of nanomaterials with blood plasma proteins has been investigated in most detail due to its importance in drug delivery, circulation time, organ distribution, and clearance (Karmali and Simberg, 2011). Protein adsorption and dissociation is a complex, dynamic phenomenon (Cedervall et al. Quantitative techniques to predict and characterize protein adsorption have been developed (Xia et al. Mucus is a complex glycoprotein composed of hydrophilic, dispersed regions and hydrophobic, globular domains. Most of the mechanistic studies use a variety of in vitro cellular toxicity assays and relatively high concentrations for 24 to 48 hours of exposure. As discussed in detail below, extrapolation from these short-term, high-concentration exposures in vitro to chronic, low-dose exposures in vivo is problematic. Both gram-negative and gram-positive bacteria have thick cell walls composed of complex lipids and peptidoglycans, respectively. Bacteria do not actively take up particulates; however, several investigators have shown direct physical penetration of bacterial Table 28-4 In Vitro Mechanisms of Nanoparticle Toxicity 1. The kinetics and mechanisms of cell uptake vary depending on the target cell, size, shape, and surface modifications (Chithrani, 2010). Dysregulated intracellular calcium ion homeostasis may be the consequence of influx across a damaged plasma membrane permeability barrier or release of calcium ions from the major intracellular storage sites, mitochondria, and endoplasmic reticulum. Sustained elevation in intracellular calcium can cause cell death by necrosis (Xia et al. A "hierarchical stress response" to oxidantinduced injury has been proposed by Nel et al. Macrophages are the initial cells to phagocytize inhaled particulates deposited in the airways or alveoli (Geiser, 2010). Rigid, high aspect ratio nanomaterials also cause permeabilization of the lysosomal membrane resulting in release of cathepsins in to the cytoplasm and activation of the inflammasome (Hamilton et al. Cathepsins are proteases active at neutral pH and can cleave precursors of proinflammatory cytokines that can initiate inflammatory reactions in the lungs (Biswas et al. Activation of the inflammasome, the cytoplasmic protein complex where this proteolytic cleavage and activation occurs, is also triggered by uptake of crystalline minerals including silica and asbestos fibers (Dostert et al. Adsorption of bacterial lipopolysaccharide or endotoxin (a component of the cell wall of gram-negative bacteria) is a major concern because even low levels of endotoxin can activate macrophages and dendritic cells (Vallhov et al. In all toxicological studies, well-characterized positive and negative reference samples should be included over a range of doses and exposure times. Complete materials characterization is required for adequate interpretation of toxicological studies (Warheit, 2008; Stone et al. Nanotoxicologists must collaborate with chemists, engineers, and materials scientists in an interdisciplinary research team in order to understand the chemical, physical, and structural properties responsible for biological interactions and potential toxicity of nanomaterials. The relevance of in vivo extrapolation from high-dose, short-term, in vitro toxicity assays is discussed in more detail below. A long-term goal of mechanistic nanotoxicology is to reveal structure-activity relations that may allow the design of safe nanomaterials through re-engineering or reformulation (Hutchison et al. As will be discussed later, a common problem with in vitro studies is that very high doses/concentrations in culture media are used that have no relevance for realistic in vivo conditions. Moreover, results of in vitro assays can be misleading due to interference of the nanomaterials to be tested with the testing reagents, adsorption of induced mediators (Worle-Knirsch et al. These mineral-based sunscreens cause less skin irritation and produce fewer allergic reactions than chemical-based sunscreens. Only superficial penetration in to the upper layers of the epidermis was observed and no zinc or titanium above untreated control levels was observed in the perfusate (Monteiro-Riviere et al. Table 28-3 summarizes several of these properties that are known to affect biological/toxicological effects. The size and size distribution are important determinants-thermodynamic and aerodynamic-for the deposition efficiency of inhaled materials throughout the respiratory tract. The formation of agglomerates of aerosols (coagulation) depends on their number concentration in the airborne state and is a function of time (Hinds, 1982). The effect of such time-dependent agglomeration on decreasing the number of airborne particle concentration and on increasing the overall particle size is illustrated in Table 28-5 assuming simple monodisperse coagulation in still, undisturbed air. For example, it takes only 20 s for a very high number concentration of 1014 particles/cm3 to decrease by half, whereas it takes 231 days if the initial concentration is only 100 particles/cm3. Similarly, in order to double the initial particle size because of a resulting increase in the agglomerate particle size, it takes 140 s for the initially very high concentration, but four years for the low concentration. For example, the specific density of TiO2 is 4 g/cm3, whereas the bulk density (density of a powdered material including interparticle spaces) of nano-TiO2 depending on primary particle size ranges from 0. The volume of the measured mass/cm3 includes the particle volume, the interparticle void volume, and any internal pore volume. In simple general terms, the aerodynamic diameter (Dae) of an aerosol is correlated with the physical geometric particle diameter (Dgeom) as Dae = Dgeom × rho (rho = material density in g/cm3). Uptake in to cells is influenced by their surface charge, surface reactivity, the chemistry of surface coatings [functional groups, polymeric coatings] and also surface defects to the material as-synthesized, or introduced during surface functionalization or processing such as acid purification or ultrasonication for dispersion). The same ionic concentration outside the cell will elicit no or only a modest response because of selective cell barriers preventing metal ions from entering the cell. The cautionary note is more generally directed toward the extrapolation of in vitro-based oxidative stress results to in vivo conditions. Alterations can occur through oxidation or dissolution (above), or through adsorption of proteins and lipids once they have been taken up in to different compartments of the organism, has become an important area of research (Cederval et al. Toxicologists are used to thinking in units of mass or molarity when characterizing a dose or concentration. A significantly greater influx of inflammatory neutrophils in to the lung was induced by 25 nm TiO2 per unit mass than by 250 nm TiO2. The result is a very steep dose­response for the nanosized TiO2 and a flatter dose­response for the larger TiO2. Likewise, there was a clear separation of the dose­response when based on the number as dosemetric; however, when the same data were expressed based on particle surface area, a common dose­response relationship emerged. Although the concept of particle surface area as dosemetric is biologically plausible because it is the surface of particles that interacts with cell structures, the total surface area may only be a surrogate of the actual biologically relevant surface. As was discussed above, there are a number of surface properties (Table 28-3) that affect interaction with cells. Thus, identifying a biologically available surface area will be of great value for defining a proper dosemetric. Both the external and existing inner surface (porosity) in pores larger than the nitrogen molecule are determined by this technique. There is a need for standardization of the method with regard to the use of nitrogen or other gases (Kr; Ar) because different molecule sizes will "see" and report different surface areas in molecular-sized pores (<0. Inflammatory cell response (neutrophil number in lung lavage of rats 24 hours after intratracheal instillation of two sizes of TiO2 particles expressed by different dosemetrics. Based on the results of these studies, Morrow (1988) formulated a "particle overload" hypothesis: When the volume of phagocytized particles in alveolar macrophages exceeds 6% of the normal macrophage volume, their physiological clearance function becomes impaired; if the phagocytized volume reaches 60%, the clearance function ceases completely. Pauluhn (2010) has applied this volumetric overload concept to results of a well-performed subchronic rat inhalation study for estimation of a human occupational exposure limit. Follow-up studies to the mechanistic basis of lung particle overload point to particle surface area of agglomerated phagocytized nanosized and larger particles as dosemetric, which appears to correlate better with the impaired clearance function of alveolar macrophages rather than the phagocytized volume (Oberdörster et al. Among the different dosemetrics discussed in this section, particle number is of particular importance with respect to characterizing exposure. Exposure concentrations in the air are expected to be very low, which makes it difficult to determine the precise concentration based on measuring mass. However, although these correlations can readily be established for dry powders, even when they consist of polydisperse particle sizes, these correlations will change upon inhalation and disposition in the body because of different deposition and biodistribution efficiencies in the lungs and other organs. Because the respiratory tract is a major route for humans to exposure of nanomaterials, the following sections will focus on this portal of entry to discuss biokinetics, effects, and concepts for in vivo and in vitro toxicity testing. However, inhalation is the only physiological method and should be considered the gold standard for exposure to airborne materials. Obvious major differences between bolustype and inhalation exposures relate to the dose rate (see discussion later), use of anesthesia, the distribution of administered material within the respiratory tract, and the need for special expertise and equipment required for inhalation but not bolus-type exposures. For medical application, injection (intravenous, intramuscular, subcutaneous, and other) will also be an important entry route in to the organism. But: Requires thorough understanding of differences between both methods to avoid misinterpretation of instillation results. The authors also mention situations when instillation should not be considered: For determining deposition pattern in lung to mimic inhalation; toxic effects in the upper respiratory tract; not to use for materials that react with vehicle; they also cautioned that short-term clearance (mucociliary) is not reflected accurately. Of special importance is the tremendous difference in the delivered dose rate: Bolus-type delivery occurs within a fraction of a second, whereas inhalation at realistic concentrations takes hours to months of exposure in order to deposit the same dose in the lung. Treating a dose delivered by bolus to be the same as a dose that has accumulated in the lung over a life-long exposure is scientifically not justifiable and needs to be discouraged (Oberdörster, 2012). Consequently, underlying mechanisms of effects induced by such unrealistic high doses are different from those induced by relevant doses and dose rates (Slikker et al. The difference in dose rate is four to five orders of magnitude, with a strong inflammatory response at the highest dose rate (instillation) and no response at the lowest dose rate (inhalation). Evidence for such adaptation following inhalation exposure to nanosized particles in humans was already reported eight decades ago when Drinker et al. Adapted rats show no inflammatory response assessed by neutrophil cells in lung lavage, nonadapted rats develop severe lung injury after 15 minute. Bolus-associated problems have been discussed above, and confirmation of results from such "proof of principle" studies by follow-up inhalation studies is desirable. This concept states that the physicochemical properties of nanomaterials, such as size, surface properties, shape, dissolution, and others when in contact with media in the different body compartments determine protein and lipid adsorption and desorption patterns and thereby influence biodistribution across barriers and in target tissues and cells. The three different methods of bolus-type dosing of the respiratory tract-intranasal instillation; intratacheal instillation; oropharyngeal aspiration-represent a convenient way to obtain first or preliminary data about effects in the respiratory tract. The limitations and caveats of using these modes of administration- as pointed out in the preceding paragraphs-should be taken in to account when interpreting the results. Immediate short-term inflammatory responses will be induced, and these early bolus-associated effects are likely to also influence long-term effects. Adaptive responses are important physiological protective mechanisms, which need to be considered when interpreting results of nanomaterial toxicity testing. Despite the limitations of bolus-type delivery, they may be viewed as "proof of principle" or "hypothesis-forming studies," with the findings to be confirmed by subsequent inhalation studies. Other in vivo bolustype deliveries involve intravenous, intraperitoneal, or intrapleural injections. Physicochemical properties of nanomaterials influence the adsorption of proteins and lipids from different organs, which affect the biodistribution of nanomaterials. This makes it very difficult to determine the actual exposure concentration because it continually decreased, and changes in particle size due to rapid settling of the aerodynamically larger particles will occur. A dynamic exposure system with continuously generated aerosol is the standard and preferred method for inhalation exposures. There is good general agreement between results of the two models, although some quantitative differences exist. It should be kept in mind that these are still models to estimate the deposition in the respiratory tract depending on particle parameters, airway geometrics, and breathing modes. Interindividual time values can be very different from the averages that are calculated by the models. For both species nasal breathing is assumed, which is the obligatory mode for rats. Comparing deposition efficiencies between rats and humans, similarities but also differences become obvious: Qualitatively, size-dependent deposition fractions are similar; for example, there is a lowest point of deposition for inhaled particles in both species around the size of 1 Deposition fractions 0. The deposition efficiency of inhaled particles depends on several particle characteristics, the anatomical structure of the airways, and breathing parameters. Particle size, size distribution, density, and shape are most important for their aerodynamic and thermodynamic diameter, which govern deposition in the respiratory tract by inertial impact, gravitational settling, and displacement by diffusion. In addition, interception (in particular for elongated structures or fibers) and electrostatic image forces (positive charge on particles attracted by negative epithelial surface) play a role in certain conditions (see Chap. Because in vivo toxicological studies are mostly performed in experimental animals, and because of anatomical and some physiological differences in the respiratory system, knowledge about variations in the behavior of inhaled particles is essential for interpreting results of animal inhalation studies with respect to dosimetric extrapolation to humans. Several particle deposition models have been developed based on mathematical modeling and supported by results of numerous human studies using inhalation of benign particles of different sizes. These data have been incorporated in to mathematical equations describing airborne particle behavior due to impaction, sedimentation, 10­3 100 10­2 10­1 Particle diameter, m Rats Total 101 102 1 0. Model predictions of deposition fractions for different particle sizes in humans and rats.

This approach is not preferred erectile dysfunction generics purchase 20 mg adcirca with amex, but use of isotopic labels now is readily feasible when coupled to ultrasensitive detection by accelerator mass spectrometry (Buchholz et al impotence caused by medication order genuine adcirca. For in vitro work erectile dysfunction medications injection buy adcirca no prescription, excised split-thickness skin can be employed in special diffusion chambers erectile dysfunction age 21 buy discount adcirca online, though care is needed to preserve the viability of the living layer of epidermis erectile dysfunction treatment tablets adcirca 20 mg buy on line. The chemical is removed for measurement from the underside by a fluid in to which it partitions, thereby permitting continued penetration. Commonly employed is a simpler setup using cadaver skin with the lower dermis removed. This lacks biotransformation capability, but retains the barrier function of the stratum corneum. Accurate testing of percutaneous absorption of poorly soluble chemicals from environmental and pharmaceutical substrates requires attention to details of particle size, component complexes, vehicle, application rate, and skin contact. A long time goal has been to predict chemical permeability from chemical structure. Comparisons of predictive models with results from transdermal patches show good correlations, despite large discrepancies in fluxes of some compounds, and emphasize the importance of experimental details (Farahmand and Maibach, 2009). In specific activity, phase I metabolism in the skin usually is only a small fraction (3%) of that in the liver (Rolsted et al. Biotransformation influences the biological activity of xenobiotics and topically applied drugs, leading to their degradation or their activation as skin sensitizers or carcinogens (Svensson, 2009). In fact, a large fraction of the pharmaceuticals used in clinical dermatology are cytochrome P450 inducers, inhibitors, or substrates (Ahmad and Mukhtar, 2004). For example, cytochromes P450 1A1 and 1B1 are inducible in the epidermis to high levels by crude coal tar (Smith et al. Exposure to such inducers could influence skin biotransformation and even sensitize epidermal cells to other chemicals that are not good inducers themselves, a phenomenon observable in cell culture (Walsh et al. Biotransformation of a variety of compounds in the skin has been detected, including arachidonic acid derivatives, steroids, retinoids, amines, and polycyclic aromatic hydrocarbons, suggesting that multiple P450 activities are expressed. Using sensitive Measurements of Penetration A pharmacokinetic approach with intact subjects has been commonly employed with experimental animals. To simplify determination of penetration kinetics, technologies, it is now evident that numerous distinct isozymes are expressed at widely varying levels. For example, measured ethoxycoumarinO-deethylase activity is 20-fold higher in mouse than human (or rat) skin. Differences of such magnitude help rationalize the observation that the rate of penetration of ethoxycoumarin is sufficient to saturate its metabolism in some species such as human but not in others such as mouse or guinea pig (Storm et al. Beyond the cytochromes P450, other phase I enzymes expressed in the skin include flavin-dependent monooxygenases, aldehyde dehydrogenases, carboxylesterases, and glutathione peroxidases (Hu et al. In general, this activity occurs at a lower rate than observed in the liver, but exceptions are evident, as in the case of quinone reductase (Khan et al. Different species express different relative amounts of the various isozymes, which could alter resulting target specificities or degrees of responsiveness. Glutathione S-transferase, for instance, catalyzes the reaction of glutathione with exogenous electrophiles or provides intracellular transport of bound compounds in the absence of a reaction. It also facilitates the reaction of glutathione with endogenous products of arachidonate lipoxygenation (leukotrienes) to yield mediators of anaphylaxis and chemotaxis, which are elements of the inflammatory response in skin. Of the first three major transferase forms characterized in liver, the dominant form in skin of humans and rodents is the P isozyme. A comparison of human with rodent skin indicates the former has higher glutathione S-transferase activity but lower glutathione content, suggesting that it may be less susceptible to low doses of electrophilic substrates, whereas rodent skin could be less susceptible at higher doses when glutathione is depleted in human but not mouse skin (Jewell et al. A variety of other metabolic enzyme activities have also been detected in human epidermal cells, including sulfatases, -glucuronidase, N-acetyl transferases, esterases, and reductases (Hu et al. In addition, the intercellular region of the stratum corneum has catabolic activities (eg, protease, lipase, glycosidase, and phosphatase) supplied by the lamellar bodies along with their characteristic lipid (Elias, 1992). The epidermis and pilosebaceous units are the most important drug targets and sites of toxic effects sites and, indeed, are the major sources of biotransformation activity in the skin. However, other cell types such as fibroblasts are known to participate in biotransformation, helping to rationalize observations that organotypic cell cultures containing underlying fibroblasts resemble natural skin in biotransformation better than those without fibroblasts (Gibbs et al. Such cultures, where keratinocytes float on collagen gels at the air­liquid interface, are better skin mimics than conventional ones using established keratinocyte lines. Their development has stimulated aspirations that these in vitro models can replace much animal testing of cosmetics and potential skin toxicants. The influence of hydroxysteroid dehydrogenases and microsomal reductase activities during percutaneous absorption is evident in studies on skin in organ culture. Biotransformation can activate prodrugs, an example being minoxidil, applied to prevent hair loss, which undergoes sulfation locally to its active form. To permit increased penetration of pharmaceuticals through the lipid barrier of the stratum corneum, prodrug design strategies have been developed that depend on epidermal esterase activity. Thus, hydrophobic esters of pharmaceuticals targeting the skin (eg, acne) could be applied to the skin surface, de-esterified during transit, and yield slow release of the active forms (Fang and Leu, 2006). Using eczema of the hand as a sentinel condition, since 80% of the total reported dermatitis occurs at that location (10% on the face), reveals a prevalence of 7% to 10% among workers. Attributed to better diagnosis, more accurate identification of offending chemicals, and more effective prevention and worker education, the fraction of afflicted workers recovering without impairment has improved nearly to 80% with proper management (Belsi to , 2005). However, while certain conditions carry a favorable prognosis, others (eg, chronic cumulative irritant contact dermatitis or contact allergy to nickel, chromate, formaldehyde, or rubber) frequently result in chronic disease in which changing jobs is of limited or no benefit (Belsi to , 2005; Emmett, 2003). Overall, contact dermatitis falls in to the two major categories of irritant and allergic forms that share important features (Watkins and Maibach, 2009). Both involve inflammatory processes and can have indistinguishable clinical characteristics of erythema (redness), induration (thickening and firmness), scaling (flaking), and vesiculation (blistering) in areas of direct contact with the chemical. Biopsies from affected sites reveal a mixed-cell inflammatory infiltrate of lymphocytes and eosinophils and spongiosis (intercellular edema), but are insufficient to distinguish the two conditions from each other or from certain other common syndromes. For example, since wet cement is alkaline and often contains chromates (commonly allergenic), chronic exposure can produce a composite response. Irritant Dermatitis Accounting for nearly 80% of contact dermatitis cases, this condition arises from the direct action of agents on the skin. A chemical in this category is anticipated to give an adverse reaction to anyone if the concentration is high enough and the exposure time long enough. Certain chemicals at sufficient concentration produce an acute irritation, sometimes called a second-degree chemical burn, that can even result in scarring in serious cases. These include strong acids, alkalies, and powerful oxidizing and reducing agents that substantially disrupt the cornified layer, producing cytotoxicity directly. The chronic friction and production of small scale trauma can wear away the lipid barrier of the stratum corneum, leading gradually to further damage (loss of cohesion, desquamation) that facilitates penetration of exogenous chemicals and may be detectable as increased transepidermal water loss. Chronic exposure in the occupational setting often elicits a process of "hardening," where the irritant response resolves. Of uncertain mechanism, it exhibits thicker granular layer and stratum corneum, increased permeability to irritants, altered expression of inflammatory mediators, and a parallel hardening of unexposed skin (Watkins and Maibach, 2009). In any case, increased penetrance at sites of barrier damage can facilitate exposure to chemicals that elicit subsequent toxic effects. Eyelids have a thin epidermis and are quite sensitive, for example, and the back is more sensitive than the forearm or the scalp of individuals with male pattern baldness (Zhai et al. The incidence of atopic dermatitis is increasing rapidly in industrialized societies, and now comprises up to 20% of the pediatric population in these societies (Elias and Schmuth, 2009). Atopic individuals are the most sensitive to irritants and exhibit a propensity to produce specific IgE antibodies to allergens and typically suffer from hay fever. These individuals usually have a poorer prognosis than nonatopics and have a higher frequency of persistent dermatitis. The best preventive measure for atopics and others is to avoid exposure to contact irritants, but in practice this strategy is difficult to implement. That atopic dermatitis has a strong genetic component led to the realization that defects in the intermediate filament aggregating protein filaggrin are strongly associated with this condition and associated development of asthma (Palmer et al. That loss of filaggrin also causes ichthyosis vulgaris, a scaly skin condition with defective epidermal barrier function (Gruber et al. Information on the irritancy of chemicals toward human skin may be obtained as part of differential diagnosis by patch testing for allergic response. The skin of laboratory animals (mice, rats, rabbits, and guinea pigs) can be used for testing, but it is thinner and more sensitive than human skin to irritants. For development of new pharmaceuticals, cosmetics, and other consumer products, a great need exists for an in vitro system to determine the potential for irritant responses. Use of human epidermal cell cultures has been increasing as reconstructed epidermal and skin models come closer to the native differentiated state. For example, a recent study compared 50 chemicals for which data on 30 are available from patch testing (Tornier et al. Such models offer advantages in convenience and cost, appear applicable to phototoxicity as well, and are more uniform in response than skin in the human population. Although advanced, the state of maturation in such culture models is not complete, as seen by histology and barrier function, resulting in their greater sensitivity than the skin (Netzlaff et al. In addition, extrapolation of the models to cumulative insult dermatitis presents a challenge. A more immediate threat is chemical assault on individuals, a worldwide problem resulting in serious disfigurement and visual impairment (Milton et al. Acids, typically those readily available (sulfuric, nitric, sometimes formic), are the most common agents, and the face is the most common target. To induce sensitization through the skin, chemical haptens generally penetrate the lipid barrier and, to be detected by the immune system, become attached to carrier proteins. The Langerhans cells present the processed peptides to T helper type 1 cells in regional lymph nodes, thereby stimulating interleukin release and proliferation of the sensitive T helper cells. Over a one- to three-week period, memory T cells are thus generated and enter the circulation. Upon subsequent exposure to a specific antigen previously encountered, allergen presentation by the Langerhans cells results in a much greater response due to homing by the memory cells to the skin, their clonal proliferation and their release of cytokines chemotactic for inflammatory cells and stimulatory for their further production. Because this process takes time, the characteristic dermal infiltration and spongiosis result after a delay (latent period) of a half to several days (Mark and Slavin, 2006). Thousands of chemicals have been reported to give rise to allergic contact dermatitis, many across a variety of occupations and Chemical Burns A chemical that is extremely corrosive can produce immediate coagulative necrosis resulting in considerable tissue damage with ulceration and sloughing. Sometimes referred to as a third degree chemical burn, the damage does not have a primary inflammatory component and thus may not be classified as an irritant reaction. If the chemical is not quickly and completely removed, damage to the skin may continue and, with increased access to the circulation, systemic injury can occur. Table 19-2 lists some important corrosive agents giving chemical burns in the occupational arena. Certain chemical warfare agents first used in combat a century ago, such as bis-(2-chloroethyl)sulfide (sulfur mustard) or 2-chlorovinyl dichloroarsine (Lewisite), are potent vesicants upon skin contact and produce considerable damage when inhaled. Table 19-3 lists some common contact allergens, two of which among others are shown in. Because most chemicals in the chemical universe are only weakly active or infrequently encountered, much effort has focused on finding the major allergens in the population by systematic patch testing of dermatology patients. Although not measuring sensitivity in the population at large, the results are quite useful. The panel of chemicals tested can vary with geographic location to accommodate local usage, or it can be directed to specific anatomic sites such as the foot (Holden and Gawkrodger, 2005). Panels also are adapted to emerging trends as new products appear and others decline in use. Table 19-4 lists the 21 agents most commonly giving positive reactions in adult subjects (ages 19­64) in recent patch tests conducted by the North American Contact Dermatitis Group (Warshaw et al. The testing showed that individuals older than 64 exhibited rates similar to those in adults, both higher than those in children. Most such surveys reveal two-thirds of the subjects to be sensitive to at least one agent in the panel (Yoo et al. Increasing prevalence of reaction to nickel among younger subjects may reflect increasing exposure, including through body piercing (Schram et al. A number of agents (nickel, dichromate, p-phenylenediamine, and formaldehyde) have shown high prevalences of reactivity for several decades, while others, once thought innocuous, have more recently become recognized as reactive. For example, individuals exhibit sensitization to gold jewelry, dental gold, and gold coronary stents (Moller, 2010). As with other consumer products, reduction in use of the most prevalent allergenic chemicals and their replacement by less allergenic substitutes are advocated. Caution in using less characterized chemicals as replacements must be exercised, however, since their allergenicity may not become evident until they reach large populations of users, as has happened in several prominent cases (Uter et al. For instance, methylchloroisothiazolinone/ methylisothiazolinone, used in cosmetics, was replaced with the biocide methyldibromo glutaronitrile, which did not cause allergic contact dermatitis in initial screens. Upon widespread use, however, the latter was shown to be a potent contact allergen (Kynemund Pedersen et al. Paradoxically, several chemicals that are reliably contact sensitizing are used therapeutically for papillomavirusinduced warts, skin cancer, and alopecia areata (Holzer et al. Unlike contact irritants, where the response is generally proportional to the applied dose and time, contact allergens can elicit reactions at very small doses. In addition, the dose required to elicit a reaction is lower after sensitization with a higher dose. Moreover, the dose dependence for sensitization displays nonlinearity, suggesting that the response of individual dendritic cells is sublinear, probably sigmoidal. Thus, more stimulation can produce a more than proportionally larger response, although at high doses saturation and sometimes even inhibition of the response become evident. The findings also reveal a wide variation in human response to sensitization, which appears to have at least in part a genetic basis. Diagnosis and Testing When a patient exhibits allergic contact dermatitis, finding the responsible agent is important to avoid continued exposure.

A great deal of experimentation at many biological levels has been conducted over the last five decades to these ends erectile dysfunction exercise buy generic adcirca 20 mg. This diagram is a simplification of a more complex metabolic scheme described in detail by Lash et al erectile dysfunction injection test discount adcirca 20 mg on line. That metabolite is reabsorbed and taken up by the liver does gnc sell erectile dysfunction pills generic adcirca 20 mg free shipping, where a portion is detoxified by N-acetylation erectile dysfunction videos cheap 20 mg adcirca free shipping. Whereas substantial progress has been made on the mechanistic front erectile dysfunction drugs at walgreens discount 20 mg adcirca visa, the reader should not infer from the text that follows that all modes of action are known with absolute certainty. This may confer a growth advantage to initiated cells, and is referred to as negative selection. Bull (2000) and Moore and Harrington-Brock (2000), however, conclude that it is unlikely that those metabolites would cause tumors in any organ through genotoxicity or mutagenicity at exposure concentrations relevant to humans. Cytotoxicity is characterized by vacuolization and increased replication of these cells in the bronchiolar epithelium. This loss of metabolic activation capacity can be thought of as an adaptive response. Chloral does appear to have some genotoxic potential, especially in regard to inducing aneuploidy. However, the fact that tumors are not seen in species where cytotoxicity does not occur strongly implicates cytotoxicity and reparative proliferation in tumor formation. In all strains of rats tested, cytomegaly and karyomegaly of tubular cells in the renal corticomedullary region were seen. Frank toxic nephropathy was observed with higher frequency in male rats beginning at 52 weeks of exposure. Renal adenomas or adenocarcinomas were occasionally seen in male rats of different strains after two years of the repetitive, high-dose oral exposure regimen. Cellular proliferation, accompanied by increased expression of proteins associated with cellular growth, differentiation, stress and apoptosis, was also an early response to low doses. Tubular necrosis ensues, with subsequent proliferation that can alter gene expression, which may modify cell growth and differentiation. Mechanisms of noncarcinogenic and carcinogenic action are discussed in detail by Lash et al. The question of whether chronic tubular damage is a prerequisite to renal tumor formation is quite important. Results showed a significant increase in cell proliferation in renal tubular cells but no increase in preneoplastic renal lesions or tumor incidence. Cumulative excretion of the N-acetyl derivative was seven- to eight-fold higher in the rats. A reassessment by the investigators of a larger population, however, revealed no such relationships (Wiesenhutter et al. These observations show data congruence, indicating that the conjugation pathway plays a central role in induction of renal carcinoma in males of both species. Most of the epidemiology studies in the United States prior to 2000 involved workers in the aircraft maintenance and manufacturing industries. There were also investigations of Swedish, Finnish, German, and Danish worker cohorts. Results of these assessments have been mixed, ranging from no association to limited evidence. By the closing date of the study, five of the 169 exposed workers had been diagnosed with kidney cancer versus none of the 190 controls. These workers reported frequent dizziness, requiring them to seek fresh air several times daily. More recent investigations have generally involved surveys of populations with lower exposures. Cohort studies showed associations with smoking, obesity, diminished physical activity, hypertension, and certain chemical exposures. Where adequate data are available to support reversible binding of the carcinogenic moiety to biological molecules as the initiating event, a nonlinear (ie, threshold) risk assessment/approach is to be used. Otherwise, the default assumption of a linear (ie, no-threshold) model/approach is to be used to estimate cancer risk. Despite genotoxic events, kidney tumor formation in humans is generally believed to require promotion resulting from frank cytotoxicity. Caldwell and Kesheva (2006), however, opine that there may be other modes of action of multiple metabolites operative at low doses. It concluded there was concordance between rat and human studies of renal carcinogenicity. The preponderance of evidence indicated that humans would be much less susceptible than mice to liver and lung carcinogenesis. It was recommended, among other things, that a new meta-analysis of epidemiological data be conducted. Kelsh and his coworkers recently completed meta-analyses of occupational study data. Much attention is being focused on adverse health effects that may be experienced by dry cleaners and other persons living in the proximity of such facilities (Garetano and Gochfeld, 2000). This metabolic intermediate can be biotransformed to several products (Lash and Parker, 2001). This results in peroxisome proliferation, which generates reactive oxygen moieties that can cause lipid peroxidation, cellular injury, and altered expression of cell-signaling proteins (Bull, 2000). A lack of dose dependence reflected saturation of metabolic activation in this dosage range. These alterations were accompanied by an increase in 2u-globulin, a male rat-specific protein. Proposed mechanism of solvent-induced kidney cancer in male rats involving 2u-globulin. The accumulation of 2u-globulin is cytotoxic, causing cellular necrosis and compensatory cellular proliferation in the P2 segment of renal proximal tubules (Borghoff et al. No worker exhibited clinical signs of hepatic dysfunction or abnormal serum enzyme concentrations, although there did appear to be an increase in one isozyme of -glutamyltransferse, which was said to be associated with hepatobiliary impairment. Another investigation of dry cleaners failed to reveal increases in serum enzymes, but did show mild to moderate changes in hepatic parenchyma revealed by ultrasonography (Brodkin et al. Employees of dry-cleaning shops have been the subjects of a number of studies of potential kidney effects. Increased concentrations of urinary lysosomal or -glucuronidase activity were described in dry cleaners exposed to 10 ppm (Franchini et al. Other investigators have failed to find evidence of renal effects in such populations. Laboratory tests revealed hematuria and proteinuria that lasted for 10 and 20 days, respectively. The incidence of this form of leukemia can exceed 70% in F344 controls (Caldwell, 1999; Ishmael and Dugard, 2006). The overall incidence of Leydig cell (testicular) tumors was 1056 70%, 80%, and 82% in the 0-, 200-, and 400-ppm groups, respectively. Therefore, these tumors are believed to be irrelevant to men (Ishmael and Dugard, 2006). Some researchers have reported findings of excess incidences of different cancers, while others have not. Nevertheless, there was sufficient information for Weiss (1995) to conclude that cigarette smoking and alcohol consumption could only partially account for an increased rate of esophageal cancer in dry cleaners. This study adequately characterized exposures and included a relatively large number of subjects. However, some of the assessments lacked power due to a limited number of study subjects. Knowledge of the relevance of the animal data to humans is essential in order to meaningfully extrapolate from one species to another. Accumulation of 2µ-globulin in cytoplasmic droplets elicits tubular cell necrosis and compensatory cell proliferation (Goldsworthy et al. Sustained cell proliferation can promote clonal expansion of spontaneously or chemically initiated cells in proximal tubules to form preneoplastic and neoplastic lesions (Swenberg, 1993). The increase in cell proliferation is reversible, as is the binding of halocarbon metabolites to 2µ-globulin. Melnick and Kohn (1999), however, argue that some data are inconsistent with this conclusion, and that alternative mechanisms may exist. Lash and Parker (2001) compiled an excellent review of the metabolism, toxicity, and modes of toxicity of the chemical in laboratory animals and humans. It was found in groundwater at 21% of hazardous waste sites surveyed in the United States (Pohl et al. Mice breathing high vapor levels initially exhibited increased locomotor activity, followed by decreased activity. These enzymes are released from damaged or necrotic hepatocytes in to the bloodstream. Statistical analyses were not presented, and the authors stated that definite conclusions could not be drawn from their work due to limitations in the design and number of animals. It should be recognized that workers are commonly exposed to multiple solvents in the workplace. With this approach, the prior input information can be combined to obtain posterior distributions of key model parameters. Some human hepatocytes apparently exhibit nuclear localization, others cytoplasmic (Sherratt et al. Positive results for sister chromatid exchanges, chromosomal aberrations, and the micronucleus test have been obtained in experiments with human cell lines and isolated cells. Similarly dosed male and female F344 rats exhibited mild to moderate hepatocellular lipid vacuolation and elevated serum enzyme activities at daily dosage levels as low as 166 to 209 mg/kg per day (Kirschmann et al. The male mice showed a trend for an increase in hepatocellular adenomas and carcinomas, but the modest response was not dose-dependent. There was a statistically significant increase in neoplastic nodules or hepatocellular carcinoma in some groups of female F344 rats. The number of benign mammary tumors per tumorbearing female S-D rat increased with increasing concentration of exposure, although the number of tumor-bearing rats was not significantly elevated over controls. There were weak trends for neoplastic nodules and hepatocellular carcinoma, as well as benign mammary tumors in female rats. The incidences of these hepatic and lung tumors in control B6C3F1 mice are quite high (Haseman et al. There were no increased risks of cancer mortality for all tissues or for lung or breast. This was apparently the sole report of increased hepatic cancer mortality in an occupational population. Occasionally, excess risks of other cancers have been found in highly exposed groups. Early signs of hepatocellular injury in rats include dissociation of polysomes and ribosomes from rough endoplasmic reticulum, disarray of smooth endoplasmic reticulum, inhibition of protein synthesis, and triglyceride accumulation. Single cell necrosis, evident five to six hours postdosing, progresses to maximal centrilobular necrosis within 24 to 48 hours. A variety of cytoplasmic enzymes are released from dead and dying hepatocytes in to the bloodstream. The activity of these enzymes in serum generally parallels the extent of necrosis in the liver. Both unstable radicals bind covalently to a variety of cellular components including enzymatic and structural proteins and polyunsaturated fatty acids in membranes. This results in lipoperoxidation, loss of intracellular and cellular membrane integrity, and leakage of enzymes (Plaa, 2000; Weber et al. Increased cytosolic Ca2+ levels may result from influx of extracellular Ca2+ due to plasma membrane damage and from decreased intracellular Ca2+ sequestration. Elevation of intracellular Ca2+ in hepatocytes can cause activation of phospholipase A2 and exacerbation of membrane damage (Glende and Recknagel, 1992). Elevated Ca2+ may also be involved in alterations in calmodulin and phosphorylase activity, as well as changes in nuclear protein kinase C activity (Omura et al. High intracellular Ca2+ levels activate a number of catabolic enzymes including proteases, endonucleases, and phospholipases, which kill cells via apoptosis or necrosis (Weber et al. They were not found in hepatocytes of F344 rats, Syrian golden hamsters, or three human subjects (Casanova et al. These links were four-, seven-, and 14-fold higher in cells from mice than in cells from rats, humans, and hamsters, respectively. Clara cells are present in much lower numbers in rats, and are rare in human lungs. It also produces differential upregulation of multidrug resistance proteins that are involved in export of oxidative stress products and metabolites. This early phase regeneration (arrested G2 hepatocytes activated to proceed through mitosis) is followed at 24 hours by the secondary phase of regeneration (hepatocytes mobilized from Go/G1 to proceed through mitosis) (Bell et al. There have been extensive studies of its potential genotoxic and mutagenic effects, but the results are largely negative in bacterial and in mammalian systems. There was a significant increase in hepatocellular adenomas and carcinomas in the male and female rats at the highest exposure level. Significant increases in these tumors and in adrenal pheochromocytomas were manifest in the 25- and 125-ppm male and female mice. There was a statistically significant, but more modest elevation in hepatocellular adenomas, but not carcinomas, in the 5-ppm female mice. Degenerative and necrotic hepatic changes were seen in livers of all groups of animals with liver tumors except the 5-ppm female mice. Four weeks after cessation of this treatment, most gene expression profiles returned to control levels, except fibrogenesis. More recently, mice exposed daily for 7, 14, and 30 days were found to have a robust regenerative response in target tissues, which prevented the progression of injury (Anand et al.

Not surprisingly erectile dysfunction urinary tract infection discount adcirca, it is possible to perturb this complex series of events and thus disturb the process and purpose of reproduction erectile dysfunction and diabetic neuropathy purchase adcirca 20 mg visa. Indeed erectile dysfunction statistics uk buy adcirca online pills, all these processes can be targets for the action of specific chemicals that can disturb these events leading to adverse effects on reproduction erectile dysfunction 22 adcirca 20 mg purchase free shipping, such that the normal production of viable offspring cannot occur erectile dysfunction electric pump generic adcirca 20 mg with amex. It is thus important to consider in an evaluation of reproductive toxicity that while simple yes/no answers as to whether a particular agent can be a reproductive toxicant are possible, and indeed are used, any description of such toxicity has to be in the context of the life stage of exposure and effect. There are examples of chemicals that can have different effects on reproduction, at different life stages, via different modes of action/ mechanisms. Indeed, it might be useful for this particular aspect of Table 20-2 Examples in Which the Reproductive Strategy of the Rat Differs From That of the Human 1. The rat placenta lacks aromatase; estrogen is produced during pregnancy by the ovary. The female rat displays sexual receptivity only during estrus after "lights out" after a proestrus vaginal smear. Humans have a menstrual cycle approximately 28 days in duration and do not display periods of peak behavioral estrus during the cycle. Corpora luteal function is sustained for approximately 10 days by mating-induced cervical stimulatory prolactin surges in rats, whereas the human menstrual cycle has a spontaneous luteal phase of 10 to 14 days after ovulation. Male rat sex behavior can be induced by estrogens and involves multiple series of ejaculations in a single mating. Mating involves approximately 10 mounts, with intromission before each ejaculation, followed by a postejaculatory interval before the onset of the next series. In nonhuman primates and presumably humans, male sex behavior is androgen mediated. Both ovaries spontaneously release several ova in response to a luteinizing hormone surge in to separate uterine horns, each with a separate cervix in the rat; whereas in women, a single ovum is typically ovulated during each cycle. Spontaneous reproductive malformations are very rare in the rats, whereas in humans, some malformations such as cryptorchidism occur in 3% of newborn boys. Spermatogenesis begins at approximately 5 days of age in the rat; the spermatogenic cycle is about 53 days of age, and sperm appear in the epididymis at about 55 days of age. In humans, spermatogenesis begins during puberty at 10 to 14 years of age, and the entire spermatogenic cycle is approximately 75 days in duration. In humans, puberty occurs at 9 to 12 years of age in girls, and 10 to 14 years of age in boys. Fertility begins to decline in the female rat at about 6 months of age, especially if never mated and allowed to cycle continuously. Fertility begins to decline in women at about 35 years of age, and at 40 years of age, approximately 50% of women are infertile. Rather than provide a laundry list of chemicals that can produce effects on reproduction, one or two examples will be mentioned to illustrate the variety of processes that can be affected with referral to more detailed references. While reviewing the mammalian reproductive cycle one could start in any position, we have decided to begin with the development of the reproductive system in utero that occurs with the process of sexual differentiation of the embryo and the move forward around the cycle as depicted in. Fetal testosterone level Male external genital differentiation & growth Genital tubercle formation Leydig cell activity Sertoli cell activity Germ cell migration In rodents, the embryo remains sexually indifferent and possesses both male and female reproductive tract primordia until embryonic day 13. Gonadogenesis begins with proliferation of the mesodermal (coelomic) epithelium, which invades the underlying mesenchyme, resulting in a longitudinal thickening on the medial side of the mesonephros, known as the gonadal ridge (Byskov, 1986). The invading epithelium begins to form primitive sex cords in the gonadal ridge, which are surrounded by undifferentiated mesenchyme (Pelliniemi, 1975). Primordial germ cells, or primitive sex cells, are first visible in the fourth week in the caudal region of the yolk sac near the origin of the allantois and migrate along the hindgut, up the dorsal mesentery and in to the gonadal ridges (Eddy et al. The primordial germ cells divide mitotically during migration and continue to proliferate as they migrate under the underlying mesenchyme and are incorporated in to the primary sex cords (Moore, 1982). In the rodent, formation of the gonadal cords is a rapid process that occurs at gestational day 13 via transitory epithelial cell aggregates along the length of the gonadal ridge (Paranko et al. Gonadal differentiation is dependent on signals from the Y chromosome, which contains the genes necessary to induce testicular morphogenesis. The first morphological sign of testis formation is the aggregation of primordial germ cells and somatic cells (primitive Sertoli cells). These aggregates develop from the gonadal blastema in to plate-like structures, which then develop in to simple arches of elongated testicular cords (Paranko et al. Throughout differentiation, the testicular cords remain connected to the basal portion of the mesonephric cell mass. The cords gradually transform and extend in to the medulla of the gonad, where they branch and anastomose to form a network of cords, known as the rete testis (Moore, 1982). A characteristic and diagnostic feature of testicular development is development of a thick fibrous capsule, the tunica albuginea. As this capsule develops, the connection of the prominent testicular (seminiferous) cords with the surface epithelium is disrupted. Gradually the testis separates from the regressing mesonephros, becoming suspended by its own mesentery. These interstitial Leydig cells produce the male sex hormone testosterone, which induces masculine differentiation of the Wolffian duct and external genitalia. Intratesticular vasculature differentiates in the gonadal mesenchyme along with the growth of epithelial components. A testis-specific distribution of blood vessels is obvious from an early phase of testicular development (Pelliniemi, 1975). The fetal testis is composed of testicular cords containing supporting immature Sertoli cells and centrally placed spermatogonia, derived from the surface epithelium and primordial germ cells, respectively. These cords are surrounded by a highly vascularized interstitium containing fetal Leydig cells and mesenchyme (Pelliniemi and Niei, 1969). The seminiferous cords turn in to tubules when the Sertoli cells undergo terminal differentiation. This occurs after birth when they finish dividing (roughly at the onset of puberty). They develop tight junctions between adjacent cells, and apical secretion of fluid begins as these cells become highly polarized. In the rodent and human species, fetal testicular androgen production is not only necessary for proper testicular development and normal male sexual differentiation, but also differentiation of the Wolffian ducts in to the epididymides, vasa deferentia, and seminal vesicles (Wilson and Lasnitzki, 1971; Veyssiere et al. Near the testis, some tubules persisting and are transformed in to efferent ductules, which open in to the mesonephric duct, forming the ductus epididymis. Distal to the epididymis, the mesonephric ducts acquire a thickening of smooth muscle to become the ductus deferens, or vas deferens (Moore, 1982). In the human, the external genitalia are indistinguishable until the ninth week of gestation, and not fully differentiated until the twelfth week of development. Thus male, but not female, reproductive tract development is totally hormonally dependent and thus inherently more susceptible to endocrine disruption (see section "Endocrine Disruption [Including Screening and Puberty]"). Labioscrotal (genital) swellings and urogenital (urethral) folds then develop on each side of the cloacal membrane. In response to testicular androgens, the phallus enlarges and elongates forming the penis while the labioscrotal swellings ultimately form the scrotum. At the end of the sixth week of gestation, the urorectal septum fuses with the cloacal membrane dividing the membrane in to a dorsal anal and a ventral urogenital membrane. Approximately a week following, these membranes rupture forming the anus and urogenital orifice, respectively (Moore, 1982). Fetal testicular androgens are responsible for the induction of masculinization of the indifferent external genitalia. The testis remains caudally positioned during the 10th to 15th week until entry in to the inguinal canal and transabdominal descent. Testicular descent through the inguinal canal begins in the 28th week, and the testes enter the scrotum by the 32nd week. There are two critical phases of testis descent, transabdominal and inguinoscrotal, essential to move the testes in to the scrotum. Cryptorchidism or undescended testes occur in about 3% of full-term and 30% of preterm males making it the most common human birth defect (Boisen et al. However, in a comparative study of the prevalence of cryptorchidism in cohorts of children in Denmark and Finland a higher prevalence of cryptorchidism was observed in Denmark, with a 9% incidence rate in full-term males reported at birth (Boisen et al. These data add further evidence to the concept that there is a significant geographical difference in male reproductive health in two neighboring countries, and therefore potential exposure to similar environmental effects. As the major difference was found in the milder forms of cryptorchidism, an environmental rather than a genetic basis for effect is favored. If correct, there is a need to determine the nature of the environmental agents responsible, because similar agents Formation and production of gametes in mammals begin in early embryonic life with the development of primordial germ cells in the genital ridge and movement of these cells in to what will become the gonads (see the "Reproductive development and sexual differentiation" section). Thus, it is not surprising that the general outline applies to both mammalian males and females. The mammalian oocyte begins meiosis during fetal development but arrests part-way through meiosis I and does not complete the first division until ovulation; the second division is completed only if the egg is fertilized. Oogenesis therefore requires several start and stop signals and, in some species (eg, the human), may last for more than 10 years. In contrast, male meiosis begins at puberty and is a continuous process, with spermatocytes progressing from prophase through the meiotic second division in little more than a week. This difference in strategy has implications for the action of toxicants and critical time periods when these cells may be vulnerable to attack (see section on male and female reproductive system). Critical to this is the understanding that the complement of oocytes available to the mammalian female is complete at birth, whereas in the male there is significant stem cell (spermatogonial) renewal to maintain the significantly higher number of germ cells available in males. In addition, in many mammalian species, including humans and rats, males of the species engage in more aggressive play than do females (Hines, 2003; Hotchkiss et al. In rats, play behavior is displayed for a period of a few weeks around 35 days of age and males engage in more rough and tumble aggressive play than do females. This behavior differentiates during neonatal life and exposure to antiandrogens such as flutamide or vinclozolin shortly after birth demasculinizes this behavior such that treated males engage in female-like play at about 35 days of age. In contrast, neonatal androgen treatments masculinize female rat play behavior such that they will engage in male-like levels of rough and tumble play. Normally in rats, the development of this behavior differentiates under the influence of a neonatal surge in testosterone in the first few days of pregnancy, after which fetal testis Leydig cells regress and testosterone production declines to very low levels for a few weeks until the emergence of the adult Leydig cells occurs in the testis prior to puberty (Huhtaniemi and Pelliniemi, 1992). In rodents but not humans, interestingly the first wave of spermatogenesis is initiated at about four days of age. Emergence of the nipple buds is an event most visible around 13 days of age, which prevented in males by prenatal androgen-induced atrophy of the nipple anlagen. In addition, experimental animal data are consistent with a potential role of environmental factors in inducing altered pubertal maturation in humans. Puberty is the stage of life when an individual matures from a child, through adolescence to full maturity. The process is marked by dramatic development of hormone-dependent sexual characteristics, somatic growth, and sexual and social behaviors eventually resulting in full sexual maturity and reproductive capacity. The stages of puberty in boys and girls are determined using approaches including the Tanner Stages (Marshall and Tanner, 1969; Marshall and Tanner, 1970) for breast and pubic hair development in girls and gonadal and pubic hair development in boys. Alternatively, increasing levels of estradiol or androgens in the serum prior to some of the development of some of the early physical markers can be used to determine the onset of puberty in girls and boys, respectively. Interestingly, in most mammals including humans and rodents, puberty in the female normally precedes the age of puberty in the male. In humans, adrenarche, the maturation of adrenal endocrine function, occurs early in pubertal development resulting in the growth of pubic hair, acne, and other secondary sex traits (Auchus and Rainey, 2004). Adrenarche is independent of gonadarche and typically occurs between six and eight years of age in both sexes. Adrenarche occurs only in primates and is not associated with puberty in all primate species. Precocious puberty is defined as the onset of sexual traits before eight and nine years of age in girls and boys, respectively, whereas puberty is considered as delayed in girls if thelarche is not displayed by 13 years and at 14 years of age in boys when testicular volume of less than 4 mL (Becker and Epperson, 2006; Biro et al. Delays in boys can occur as a result of either primary hypothalamic­pituitary or gonadal failure, from head trauma or from infection. While the majority of these delays are transient, some cases are associated with gene mutations resulting in either hypogonadotropic hypogonadism or primary gonadal failure. Of greatest concern current is the observation that in the United States and several other countries the age of onset of puberty over the past 40 years has decreased from 0. Similar trends in male puberty have not been observed and similar trends have not been seen in boys. Some scientists have attributed the trends in pubertal maturation of girls to obesity rates in children. These endocrine alterations, together with elevated leptin levels and enhancement of hormonal activity by conversion of steroids to estrogens by fat cells, could affect the onset and progression of puberty in young obese girls. Premature thelarche and premature adrenarche are often referred to as pseudoprecocious puberty when the full spectrum of pubertal changes do not occur. Premature thelarche in girls and gynecomastia in boys are known to result from direct exposure to estrogen-containing personal care and "natural" products (Hertz, 1958; Massart et al. Although these conditions are usually resolved after termination of exposure, untoward consequences of these conditions may occur with prolonged exposure including shortened stature due to effects of estrogens, the growth plates of the long bones, and sexual­social behavior that is inappropriate for chronological age of the child (Wacharasindhu et al. Concerns also have been expressed that premature thelarche may enhance the likelihood of developing diseases such as breast cancer and endometriosis. Numerous human studies have examined the relationships between environmental factors and human puberty. Many studies have shown a positive relation between body fat and onset of the growth spurt, breast development, or menarche (Battaglia et al. Rodent Models of Puberty Rodents provide important animal models in the study of the genetic and environmental factors that regulate puberty. Toxicants can alter puberty as a consequence of in utero, lactational, or pubertal exposures. In a multigenerational study, discerning the stage of life when exposure induced the alteration may be challenging, if possible at all, because dosing is not initiated in the parent (F0) generation, the only generation with in utero and lactational exposure, until well after puberty.

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