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Olfactory Toxicity (Fish)
The Olfactory system is the system related to the sense of smell. In contrast, the gustatory system is the system related to the sense of taste. Many fish activities are dependent on olfaction, such as: mating, discriminating kin, avoiding predators, locating food, contaminant avoidance, imprinting and homing [9]. These activities are referred to as “olfactory-mediated.” Impairment of the olfactory system threatens survival and has been used as an ecologically relevant sub-lethal toxicological endpoint for fish [9]. Olfactory information is received by olfactory sensory neurons that are in a covered cavity separated from the aquatic environment by mucus[1]. Because they are in almost direct contact with the surrounding environment, these neurons are vulnerable to environmental changes [1]. Fish can detect natural chemical cues in aquatic environments at concentrations as low as parts per billion or parts per trillion [2]. Studies have shown that exposures to metals and pesticides can disrupt fish olfaction which can impact their survival and reproductive success [1]. Many studies have implicated copper as a source of olfactory toxicity in fishes [1] [3]. Olfactory toxicity can occur by multiple, complex mechanisms of action, an area in which further research is needed. Olfactory toxicity can be categorized by three changes in function: (1) anosmia, or inability to smell; (2) hyposmia, or a reduced capacity to smell; and (3) dysosmia, where olfactory information is processed incorrectly [1]

History
Early investigation by Hasler and Wisby (1951) examined how fish use olfactory imprinting to discriminate smells in order for fish to find their natal streams [5]. This research provided the framework for testing synthetic chemicals used by hatcheries to examine homing and straying by hatchery fish [5]. The investigation of the toxicity of mercury and copper to the olfactory systems in fish began in the early 1970s. Where they found that solutions of mercury chloride (HgCl2) and copper sulfate (CuSO4) depressed olfactory response during exposure to the two toxicants and toxicant concentration and olfactory response had an inverse relationship [4]. Olfactory toxicity can affect the ability for anadromous fish to find their natal stream causing them to stray to other streams, the implications this has for the introduction of new genes as well as returning stocks can be detrimental [5].

Olfactory System
The changes in olfactory function can be placed into three categories: (1) anosmia, the inability to smell; (2) hyposmia, a reduced ability to smell; or (3) dysomia, where olfactory signals are incorrectly processed. Most chemicals at lower concentrations cause a degree of hyposmia while at higher concentrations anosmia is the result. Lastly, dysomia is less commonly observed however cases of fish becoming attracted to metal-contaminated waters have been studied and examined (Tierney et al., 2009; Giattina et al, 1982).

Metals
Metals are a necessary and important trace element that most organisms need to function properly. They are often used as coenzymes or interact with biological enzymes to form complexes inside organisms [14]. However, if the metals in question are in too high of concentrations it can be fatal. Different parameters such as pH, alkalinity, temperature, fish size, or salinity can alter how the metals are metabolized by the organism [14]. Fish are often times less tolerant to metals than terrestrial animals are. Their gills are sensitive to changes in their environment and highly susceptible to metal toxicity (LINK) [15]. Before a metal may have toxic effects it can also cause a change in olfactory response within fish. If the exposure is short in length or low in concentration the effects can be reversed, but at high enough concentrations it becomes toxic to the organism [13]. Heavy metals mechanism of action has been hypothesized to inhibit the electrical properties of olfactory neurons by blocking ligand-gated or voltage-gated ion channels in the nervous system of fish [13].

Past Studies
A 2006 study from Japan, Olfactory inhibition and recovery in chum salmon (Onchorynchus keta) following copper exposure, focused on olfactory inhibition in chum salmon and their ability to recover from copper toxicity after being exposed to relevant copper concentrations often used on hatchery fishes. The fish were exposed to the relevant concentrations for four hours while using an EOG. Results showed that copper toxicity both depended on exposure concentration and time. A combination of these parameters, as well as other parameters, can change the degree of impact on target sites as well as if the toxic effects are reversible or not. Under short-term four hour exposures the chum salmon recovered from the toxic effects after one day. In hatchery fish this short-term effect will likely not cause harm, but in wild fish this olfactory disruption may impair important survival instincts and strategies. Based on current research a specific mechanism of action for copper toxicity has not been identified and more research is needed [13]. Another study investigated morphological changes in olfactory mucosa of Tilapia mariae when exposed to low levels of the copper toxicant. The fish were exposed to 20, 40 and 100μg/l copper for four days then allowed to recover in untreated water and were monitored during recovery. After ten full days of recovery all sample tissues tested showed no significant difference between that and the control group. This suggests that at low levels the copper damage done to the olfactory system is reversible. [16] ADDD MOREEEE

Specific Impacts
-Impacts on fish- susceptibility to Yersinia ruckeri infection in steelhead trout (M.D. Knittel, aq tox 3rd p321), loss of smell, impaired mate choosing, can’t find mating grounds/ home streams, impaired reproduction (metal meta 337)

-Copper specifically Copper can be intentionally or unintentionally introduced to fish in aquatic systems. It can be used as an effective way to prevent parasitic and fungal infections within fish populations at hatcheries [13] or it can be released from industrial, or agricultural sources. Just like other metals in aquatic systems in low enough exposures the toxic effects on fish populations can be reversed with removal of the contaminants from the ecosystem. If exposure is too high or for prolonged durations irreversible cell damage can occur which eventually leads to cell death.

Mechanism of Action
(GENERAL- I couldn’t find detailed mechanisms): Dissolved neurotoxins may: 1) compete with natural odorants for binding sites on olfactory neuron receptor proteins 2) change the activation properties of these receptors 3) move to the cytosol of the sensory neuron where the modify intracellular signaling [6]. Pesticides that act as acetylcholinesterase inhibiting neurotoxins are known to reduce the responsiveness of olfactory sensory neurons to natural stimuli [1]. The effects of these pesticides on the olfactory system is thought to be related to inhibition of acetylcholinesterase, but the role of acetylcholinesterase in the olfactory system is unknown [13]. Pesticides also are known to affect other enzymes in the olfactory system [1]. The specific mechanisms are unknown, but there is evidence that pesticides and metals have different targets in the olfactory epithelium [1].

Past Studies
Studies on pesticides and olfaction in fishes have looked at neurophysiological effects [9] [8], behavioral effects [9] [6], and reproductive effects [10] [7]. Organophosphate and carbamate insecticides are neurotoxins (link) that cause acetyl cholinesterase inhibition (link) in fish [6]. Acetyl cholinesterase-inhibiting insecticides are known to cause hyposmia [1]. Acetyl cholinesterase plays an essential role within the olfactory epithelium (link) related to mucous production [1] [6]. Diazinon (link), an organophosphate, was found to disrupt olfactory pheromone signals that induced antipredator behavior (link), such as predator avoidance [6]. It also disrupts homing behavior in Chinook salmon at environmentally-relevant concentrations [6]. Fewer diazinon-treated chinook returned to the hatchery than control fish [6]. Studies have found that olfactory sensory neurons do not respond to certain pesticides. Fish did not detect chlorpyrifos [8], esfenvalerate [8], and atrazine [9] using their sense of smell and did not avoid waters contaminated with these chemicals. This contrasts metals, which elicits an avoidance response in fish [1]. Round-up (link) was only avoided at concentrations that caused acute lethality [9]. Ovulating female salmon release a pheromone in their urine. After detection by the olfactory system of mature male salmon parr (link) plasma sex steroids (link) and milt (link) increase [10]. A synthetic pyrethroid (link) pesticide, cypermethrin, reduced or inhibited normal olfactory system response in males to the priming effect of these pheromones [10]. Atrazine, carbofuran and diazinon were also found to reduce olfactory detection of female priming pheromones by male Atlantic salmon parr [10] [7].

Specific Impacts
-Individual -Behavioral effects Chinook previously-exposed to diazinon continued to be active and feed in the presence of an alarm stimulus that represented a potential predator. Normal anti-predator behavior exhibited by controls included freezing, reduced food capture, and movement to lower areas of the water column [6]. Diazinon-exposed salmon parr would be at higher risk to predation. -Reproduction Reduced production of milt and plasma sex hormones in males due to the inability to -detect the female salmon priming pheromones [10]. -Population Survival and reproductive success of Pacific Northwest salmon may be lower in streams contaminated with neurotoxic pesticides such as diazinon [6]. These chemicals are most common in urban and agricultural watersheds, thus salmon populations in these areas may be affected. Delayed spawning in blue gill exposed to a pyrethroid was thought to be a result of disruption to the synchronization of spawning between the sexes signaled by pheromones [11]. Delayed spawning readiness in males has the potential to impact reproduction in populations. The effect of pesticides on homing ability may increase straying (link), in which fish do not return to their natal(link) streams to spawn, can lead to colonizing new habitats, but it can also diminish genetic integrity or the number of spawning animals of the original stream [6].

Mechanism of Action
Sodium laurel sulfate is an anionic detergent that has more than one probable mode of action. The interaction of SLS with mucus (, proteins, and membranes result in multiple possible modes of action [17]. The depression in olfactory sense (hyposmia) at low concentrations caused by interaction with mucus is most often a result of the disruption of mucus layers of the olfactory bulb causing avoidance behavior in rainbow trout (Onchorychus mykiss) [17].  Additionally, SLS can reversibly and irreversibly alter protein structure because they act as protein solubilizes and denaturants. This can lead to decreased enzyme activity, changes in permeability and transport characteristics of membranes [17].

Past Studies
Few studies have examined the effects of surfactants, adjuvants, and emulsifiers on fish olfaction [1]. Neurological indicators of olfactory toxicity indicate that that the surfactant sodium laurel sulfonate (SLS) at 0.5 mg/L depressed L-serine evoked responses in lake white fish (Coregonus clupeaformis) by 50% [17] [18]. Specific Impacts -Behavior Avoidance behavior exhibited by fish is species specific, Whitefish (C. clupeaformis) showed a preference toward SLS at a concentration of 0.1 mg/L while rainbow trout (Onchorynchus mykiss) and carp (C. carpio) showed an avoidance response at a concentration of 0.01 ug/L [18]. Studies are difficult to compare due to differences in test and exposure conditions [17].

Implications
The disruption of olfaction and potential effects to survival and reproductive success at environmentally-relevant concentrations of diazinon has implications for salmon recovery because this and other AChE inhibiting insecticides are commonly found in western United States streams [6]. Conventional acute and chronic toxicity testing do not explicitly address nervous system function and underestimate thresholds for toxicity in salmonids [6]. Further research needs to be done to understand olfactory toxicity. Areas where research is needed include: the effect of pesticides on the female olfactory system and reproduction, the specific mechanisms of toxicity in the fish olfactory epithelium, the impact of complex mixtures, assessing olfactory toxicity of fish in field studies (link), and the connections between sublethal effects to individuals and the effects to populations.